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    Dihydroartemisinin Inhibits mTORC1 Signaling by Activating the AMPK Pathway in Rhabdomyosarcoma Tumor Cells. Cells Dihydroartemisinin (DHA), an anti-malarial drug, has been shown to possess potent anticancer activity, partly by inhibiting the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling. However, how DHA inhibits mTORC1 is still unknown. Here, using rhabdomyosarcoma (RMS) as a model, we found that DHA reduced cell proliferation and viability in RMS cells, but not those in normal cells, which was associated with inhibition of mTORC1. Mechanistically, DHA did not bind to mTOR or FK506 binding protein 12 (FKBP12). In addition, DHA neither inhibited insulin-like growth factor-1 receptor (IGF-1R), phosphoinositide 3-kinase (PI3K), and extracellular signal-regulated kinase ½ , nor activated phosphatase and tensin homolog (PTEN) in the cells. Rather, DHA activated AMP-activated protein kinase (AMPK). Pharmacological inhibition of AMPK, ectopic expression dominant negative or kinase-dead AMPK, or knockdown of AMPKa attenuated the inhibitory effect of DHA on mTORC1 in the cells. Additionally, DHA was able to induce dissociation of regulatory-associated protein of (raptor) from mTOR and inhibit mTORC1 activity. Moreover, treatment with artesunate, a prodrug of DHA, dose-dependently inhibited tumor growth and concurrently activated AMPK and suppressed mTORC1 in RMS xenografts. The results indicated that DHA inhibits mTORC1 by activating AMPK in tumor cells. Our finding supports that DHA or artesunate has a great potential to be repositioned for treatment of RMS. 10.3390/cells10061363
    Dihydroartemisinin Modulates Apoptosis and Autophagy in Multiple Myeloma through the P38/MAPK and Wnt/-Catenin Signaling Pathways. Wu Xiuhua,Liu Yang,Zhang Enfan,Chen Jing,Huang Xi,Yan Haimeng,Cao Wen,Qu Jianwei,Gu Huiyao,Xu Ruyi,He Jingsong,Cai Zhen Oxidative medicine and cellular longevity Dihydroartemisinin (DHA), an active metabolite and derivative of artemisinin, is the most effective antimalarial drug and has strong antitumor activity in various tumor types. It has recently been reported that DHA can induce autophagy and has significant effects on multiple myeloma (MM), but the mechanisms and the relationship between the autophagy and apoptosis induced by DHA remain to be elucidated. Herein, we demonstrated that DHA significantly induces cell death in a dose- and time-dependent manner via the extrinsic and intrinsic apoptosis pathways. Moreover, DHA-induced autophagy, which plays a prodeath role in MM, can regulate canonical apoptosis and vice versa. Furthermore, the P38/MAPK signaling pathway is responsible for decreased autophagy and increased apoptosis. DHA induces autophagy and apoptosis also through the inhibition of the Wnt/-catenin signaling pathway. In addition, DHA shows a strong effect in a xenograft mouse model. Collectively, these findings reveal that DHA, as an artemisinin-based drug, could be an effective and safe therapeutic agent for MM. 10.1155/2020/6096391
    Dihydroartemisinin inhibits the growth and invasion of gastric cancer cells by regulating cyclin D1-CDK4-Rb signaling. Fan Hui-Ning,Zhu Mei-Ying,Peng Shi-Qiao,Zhu Jin-Shui,Zhang Jing,Qu Guo-Qiang Pathology, research and practice BACKGROUND:Dihydroartemisinin (DHA), a semisynthetic derivative of artemisinin, has a broad range of biological properties, including antitumor activity. However, the mechanisms by which DHA affects the tumorigenesis of gastric carcinoma (GC) are poorly understood. MATERIAL AND METHODS:The targets of DHA were identified by network pharmacology, and the association of CDK4 with clinicopathological characteristics and prognosis in patients with GC was analyzed by using TCGA data. CCK8, Transwell and flow cytometric analyses, as well as a tumor xenograft model, were used to assess the effects of DHA on the growth and migration of GC cells. qRT-PCR and Western blot analyses were used to determine the effects of DHA on the cyclin D1-CDK4-Rb signaling pathway. RESULTS:We identified 13 DHA targets and measured their expression of whichCDK4 expression levels were substantially higher in GC tissues than those in adjacent normal tissues, and high CDK4 expression acted as an independent prognostic factor of poor survival in patients with GC. DHA suppressed cell proliferation, migration and invasion in vitro and in vivo and induced G1 phase cell cycle arrest in a dose-dependent manner by regulating cyclin D1-CDK4-Rb signaling. CONCLUSIONS:DHA inhibits the tumorigenesis and invasion of GC by regulating cyclin D1-CDK4-Rb signaling and may provide therapeutic strategies for the treatment of GC. 10.1016/j.prp.2019.152795
    Dihydroartemisinin inhibits the tumorigenesis and metastasis of breast cancer via downregulating CIZ1 expression associated with TGF-β1 signaling. Li Yue,Zhou Xiaoyan,Liu Jiali,Gao Ning,Yang Ruihua,Wang Qi,Ji Jing,Ma Ling,He Qian Life sciences AIMS:Dihydroartemisinin (DHA) is currently considered as the promising cancer therapeutic drug. In this study, we aimed to investigate the anti-proliferative and anti-metastasis effects of DHA. MAIN METHODS:Utilizing breast cancer cells MCF-7, MDA-MB-231 and BT549, cell proliferation, migration and invasion were detected. RT-qPCR was performed to detect CIZ1, TGF-β1 and Snail expression, and the interactions of these related molecules were analyzed by GeneMANIA database. Western blot detected CIZ1, TGF-β1/Smads signaling and Snail expression in DHA-treated cells, in TGFβ1-induced cells with enhanced metastatic capacity, and in cells treated with DHA plus TGFβ1/TGFβ1 inhibitor SD-208. KEY FINDINGS:Results indicated DHA inhibited breast cancer cell proliferation and migration, with more potent effects compared with that of artemisinin. RT-qPCR and Western blot showed DHA inhibited CIZ1, TGF-β1 and Snail expression, and these molecules were shown to have protein-protein interactions by bioinformatics. Furthermore, TGFβ1-treatment enhanced MCF-7 migration and invasion, and CIZ1, TGF-β1/Smads signaling and snail activities; DHA, SD-208, combination of DHA and SD-208 reversed these conditions, preliminarily proving the cascade regulation between TGF-β1 signaling and CIZ1. MCF-7 xenografts model demonstrated the inhibition of DHA on tumor burden, and its mechanisms and well-tolerance in vivo; combination of DHA and SD-208 tried by us for the first time showed better treatment effects, but possible liver impairment made its use still keep cautious. SIGNIFICANCE:DHA treatment inhibits the proliferation and metastasis of breast cancer, through suppressing TGF-β1/Smad signaling and CIZ1, suggesting the promising potential of DHA as a well-tolerated antitumor TGF-β1 pathway inhibitor. 10.1016/j.lfs.2020.117454
    Dihydroartemisinin and artesunate inhibit aerobic glycolysis via suppressing c-Myc signaling in non-small cell lung cancer. Biochemical pharmacology Non-small cell lung cancer (NSCLC) cells exhibit aberrant metabolism characterized by high glycolysis even in the presence of abundant oxygen. Inhibition of aerobic glycolysis remains challenging when identifying potential cancer-specific inhibitors while maintaining or even boosting the anti-cancer immunity. Artemisinin derivatives DHA and AS have shown excellent anti-tumor and immunoenhancing roles in numerous malignancies, but the molecular mechanism of DHA and AS in regulating cancer glucose metabolism is largely unknown. In this study, we proved that DHA and AS inhibit NSCLC growth via prohibiting cancer cell aerobic glycolysis through ERK/c-Myc pathway. First, we proved that DHA and AS have comparable anti-cancer growth roles in both NSCLC cell lines and mouse Lewis Lung Cancer model. Then, our data clearly showed that DHA and AS dose- and time-dependently reduce the uptake of glucose, the production of ATP, and the secretion of lactate, the expression of glucose transporter GLUT1 and two key glycolysis-related enzymes hexokinase and lactate dehydrogenase, as well as the level of c-Myc. Finally, we generated c-Myc stable-expressing NSCLC cell line and treated it with DHA or AS, respectively. Our data clearly showed that c-Myc overexpression can partially reverse the glycolysis-repressing role of DHA and AS which strongly supported our proposal that AS and DHA suppress aerobic glycolysis in a c-Myc-dependent manner in NSCLC cells. This study extends our knowledge of artemisinin derivatives in regulating tumor glucose metabolism and provides potential strategy in the therapy of lung cancer. 10.1016/j.bcp.2022.114941
    Antitumor activity of an Artemisia annua herbal preparation and identification of active ingredients. Lang Sophia J,Schmiech Michael,Hafner Susanne,Paetz Christian,Steinborn Carmen,Huber Roman,Gaafary Menna El,Werner Katharina,Schmidt Christoph Q,Syrovets Tatiana,Simmet Thomas Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:Artemisia annua L. has gained increasing attention for its anticancer activity. However, beside artemisinin, less is known about the possible bioactive ingredients of Artemisia annua and respective herbal preparations. We hypothesized that, in addition to artemisinin, Artemisia annua preparations might contain multiple ingredients with potential anticancer activity. METHODS:MDA-MB-231 triple negative human breast cancer (TNBC) cells along with other treatment resistant, metastatic cancer cell lines were used to investigate in vitro and in vivo the anticancer efficacy of an Artemisia annua extract marketed as a herbal preparation, which contained no detectable artemisinin (limit of detection = 0.2 ng/mg). The extract was characterized by HPLC-DAD and the most abundant compounds were identified by H- and C NMR spectroscopy and quantified by UHPLC-MS/MS. Cell viability and various apoptotic parameters were quantified by flow cytometry. In vitro data were validated in two in vivo cancer models, the chick chorioallantoic membrane (CAM) assay and in orthotopic breast cancer xenografts in nude mice. RESULTS:The Artemisia annua extract, the activity of which could be enhanced by acetonitrile maceration, inhibited the viability of breast (MDA-MB-231 and MCF-7), pancreas (MIA PaCa-2), prostate (PC-3), non-small cell lung cancer (A459) cells, whereas normal mammary epithelial cells, lymphocytes, and PBMC were relatively resistant to extract treatment. Likewise, the extract's most abundant ingredients, chrysosplenol D, arteannuin B, and casticin, but not arteannuic acid or 6,7-dimethoxycoumarin, inhibited the viability of MDA-MB-231 breast cancer cells. The extract induced accumulation of multinucleated cancer cells within 24 h of treatment, increased the number of cells in the S and G/M phases of the cell cycle, followed by loss of mitochondrial membrane potential, caspase 3 activation, and formation of an apoptotic hypodiploid cell population. Further, the extract inhibited cancer cell proliferation, decreased tumor growth, and induced apoptosis in vivo in TNBC MDA-MB-231 xenografts grown on CAM as well as in nude mice. CONCLUSION:An extract of an artemisinin-deficient Artemisia annua herbal preparation exhibits potent anticancer activity against triple negative human breast cancer. New active ingredients of Artemisia annua extract with potential anticancer activity have been identified. 10.1016/j.phymed.2019.152962
    Artemisinin: A Panacea Eligible for Unrestrictive Use? Yuan Dong-Sheng,Chen Yan-Ping,Tan Li-Li,Huang Shui-Qing,Li Chang-Qing,Wang Qi,Zeng Qing-Ping Frontiers in pharmacology Although artemisinin has been used as anti-malarial drug, accumulating evidence on the extended therapeutic potential of artemisinin emerges. Apart from anti-malaria and anti-tumor, artemisinin can also exert beneficial effects on some metabolic disorders, such as obesity, diabetes, and aging-related diseases. However, whether artemisinin should be applied to treatment of the wide-spectrum diseases is debating. Here, we discuss the predisposition of a raised risk of malarial resistance to artemisinin from consideration of the multi-target and non-specific features of artemisinin. 10.3389/fphar.2017.00737
    Dihydroartemisinin as a potential drug candidate for cancer therapy: a structural-based virtual screening for multitarget profiling. Malami Ibrahim,Bunza Aisha Muktar,Alhassan Alhassan Muhammad,Muhammad Aliyu,Abubakar Ibrahim Babangida,Yunusa Abdulmajeed,Waziri Peter M,Etti Imaobong C Journal of biomolecular structure & dynamics Cancer is a rapidly growing non-communicable disease worldwide that is responsible for high mortality rates, which account for 9.6 million death in 2018. Dihydroartemisinin (DHA) is an active metabolite of artemisinin, an active principle present in the Chinese medicinal plant used for malaria treatment. Dihydroartemisinin possesses remarkable and selective anticancer properties however the underlying mechanism of the antitumor effects of DHA from the structural point of view is still not yet elucidated. In the present study, we employed molecular docking simulation techniques using Autodock suits to access the binding properties of dihydroartemisinin to multiple protein targets implicated in cancer pathogenesis. Its potential targets with comprehensive pharmacophore were predicted using a PharmMapper database. The co-crystallised structures of the protein were obtained from a Protein Data Bank and prepared for molecular docking simulation. Out of the 24 selected protein targets, DHA has shown about 29% excellent binding to the targets compared to their co-crystallised ligand. Additionally, 75% of the targets identified for dihydroartemisinin binding are protein kinases, and 25% are non-protein kinases. Hydroxyl functional group of dihydroartemisinin contributed to 58.5% of the total hydrogen interactions, while pyran (12.2%), endoperoxide (9.8%), and oxepane (19.5%) contributed to the remaining hydrogen bonding. The present findings have elucidated the possible antitumor properties of dihydroartemisinin through the structural-based virtual studies, which provides a lead to a safe and effective anticancer agent useful for cancer therapy.Communicated by Ramaswamy H. Sarma. 10.1080/07391102.2020.1824811
    Ferroptosis plays an essential role in the antimalarial mechanism of low-dose dihydroartemisinin. Li Shuo,Xu Wenhui,Wang Huajing,Tang Tian,Ma Ji,Cui Zhao,Shi Hang,Qin Ting,Zhou Hongying,Li Lanfang,Jiang Tingliang,Li Canghai Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie The activation of artemisinin and its derivatives (ARTs) to generate ROS and other free radicals is mainly heme- or ferrous iron-dependent. ARTs induce ferroptosis in tumor cells, although the involvement of ferroptosis in malaria remains unclear. We found that three typical inducers of ferroptosis (erastin, RSL3 and sorafenib) could effectively mimic DHA inhibition on the growth of blood-stage parasites, which exhibited synergistic or nearly additive interactions in vitro with DHA, while the combination of DHA with ferroptosis inhibitors (deferoxamine, liproxstatin-1) had an obvious antagonistic effect. DHA, similar to ferroptosis inducers, can simultaneously induce the accumulation of ferroptosis-associated cellular labile iron and lipid peroxide. However, deferoxamine and liproxstatin-1 reduced the increase in ferrous iron and lipid peroxide caused by DHA. These results suggested that ferroptosis might be an effective way to induce cell death in parasites and could be a primary mechanism by which DHA kills parasites, with almost 50% contribution at low concentrations. These results provide a new strategy for antimalarial drug screening and clinical medication guidance. 10.1016/j.biopha.2022.112742
    A redox-responsive dihydroartemisinin dimeric nanoprodrug for enhanced antitumor activity. Li Yawei,Pei Qing,Cui Baiji,Zhang Hongmei,Han Liu,Li Wenqing,Zhu Wenhe,Feng Xianmin,Xie Zhigang Journal of nanobiotechnology Redox-responsive drug delivery system emerges as a hopeful platform for tumor treatment. Dihydroartemisinin (DHA) has been investigated as an innovative tumor therapeutic agent. Herein, a DHA dimeric prodrug bridged with disulfide bond as linker (DHA-SS) has been designed and synthesized. The prepared prodrugs could self-assemble into nanoparticles (SS NPs) with high DHA content (> 90%) and robust stability. These SS NPs display sensitive redox responsive capability and can release DHA under the tumor heterogeneity microenvironment. SS NPs possess preferable antitumor therapeutic activity in contrast with free DHA. Moreover, the possible anti-cancer mechanism of SS NPs was investigated through RNA-seq analysis, bioinformatics and molecular biological method. SS NPs could induce apoptosis via mitochondrial apoptosis pathway, as well as glycolysis inhibition associate with the regulation of PI3K/AKT/HIF-1α signal path, which may offer an underlying therapeutic target for liver cancer. Our study highlights the potential of using redox responsive prodrug nanoparticles to treat cancer, meanwhile provides insights into the anti-cancer mechanism of DHA prodrug. 10.1186/s12951-021-01200-z
    Sustainable Antibacterial and Anti-Inflammatory Silk Suture with Surface Modification of Combined-Therapy Drugs for Surgical Site Infection. Wang Xuchen,Liu Peixin,Wu Qinting,Zheng Zhaozhu,Xie Maobin,Chen Guoqiang,Yu Jia,Wang Xiaoqin,Li Gang,Kaplan David ACS applied materials & interfaces Silk sutures with antibacterial and anti-inflammatory functions were developed for sustained dual-drug delivery to prevent surgical site infections (SSIs). The silk sutures were prepared with core-shell structures braided from degummed silk filaments and then coated with a silk fibroin (SF) layer loaded with berberine (BB) and artemisinin (ART). Both the rapid release of drugs to prevent initial biofilm formation and the following sustained release to maintain effective concentrations for more than 42 days were demonstrated. assays using human fibroblasts (Hs 865.Sk) demonstrated cell proliferation on the materials, and hemolysis was 2.4 ± 0.8%, lower than that required by ISO 10993-4 standard. The sutures inhibited platelet adhesion and promoted collagen deposition and blood vessel formation. assessments using Sprague-Dawley (SD) rats indicated that the coating reduced the expression of pro-inflammatory cytokines interleukin-10 (IL-10) and tumor necrosis factor-α (TNF-α), shortening the inflammatory period and promoting angiogenesis. The results demonstrated that these new sutures exhibited stable structures, favorable biocompatibility, and sustainable antibacterial and anti-inflammatory functions with potential for surgical applications. 10.1021/acsami.2c00106
    Co-delivery of dihydroartemisinin and pyropheophorbide-iron elicits ferroptosis to potentiate cancer immunotherapy. Han Wenbo,Duan Xiaopin,Ni Kaiyuan,Li Youyou,Chan Christina,Lin Wenbin Biomaterials Dihydroartemisinin (DHA) has shown cytotoxicity against various tumor cells in vitro in an iron-dependent manner, but its in vivo antitumor efficacy is compromised by its rapid degradation and clearance. Here we show the induction of ferroptosis by DHA in an immunogenic fashion and the maximization of in vivo antitumor efficacy of DHA by co-delivering a cholesterol derivative of DHA (Chol-DHA) and Pyropheophorbide-iron (Pyro-Fe) in ZnP@DHA/Pyro-Fe core-shell nanoparticles. ZnP@DHA/Pyro-Fe particles stabilize DHA against hydrolysis and prolong blood circulation of Chol-DHA and Pyro-Fe for their enhanced uptake in tumors. Co-delivery of an exogenous iron complex and DHA induces more ROS production and causes significant tumor inhibition in vivo. By increasing tumor immunogenicity, the combination of DHA and Pyro-Fe sensitizes non-immunogenic colorectal tumors to anti-PD-L1 checkpoint blockade immunotherapy. These findings suggest the potential of using nanotechnology to repurpose DHA and other drugs with excellent safety profiles for combination with immune checkpoint blockade to treat cancers. 10.1016/j.biomaterials.2021.121315
    Dihydroartemisinin inhibits Lewis Lung carcinoma progression by inducing macrophages M1 polarization via AKT/mTOR pathway. Xiao Xiaoqian,Li Yanping,Wang Yi,Zhang Yuxi,Chen Jilan,Liu Weiwei,Tang Jingyi,Yue Fuping,Yang Jiahui International immunopharmacology Preclinical and clinical data show a close relationship between high infiltration of tumor-associated macrophages (TAMs) and a poor prognosis in most types of tumors, thus targeting TAMs stands out as promising anticancer immunotherapies. Recent studies have demonstrated the anti-tumor effects of artemisinin via enhancing anti-tumor immunity within tumor microenvironment, but the underlying mechanism is still not clear. In the present study we uncovered an important role of dihydroartemisinin (DHA) in regulating intratumoral TAM polarization and anti-tumor immune responses in mouse Lewis Lung carcinoma model. We found that DHA inhibited Lewis Lung carcinoma progress, moderately decreased the frequencies of TAMs within tumor stroma, and significantly increased CD86 expression while decreased CD206 expression on TAMs which indicates the role of DHA in polarizing TAMs into a M1-like phenotype. Then, our in vitro data confirmed that DHA dose-dependently promoted macrophage M1 phenotype transition by increasing M1 phenotype-related molecules, meanwhile decreasing the expression of M2 phenotype-related molecules. In addition, DHA increased proinflammatory cytokine production, enhanced the phagocytic capacity while decreased anti-inflammatory cytokine production. Finally, in order to prove that AKT/mTOR signaling potentially mediated DHA-induced macrophage differentiation, we used rapamycin to specifically block the activity of mTOR and stimulated macrophages under M1 stimuli. Our data clearly showed that rapamycin significantly decreased DHA-induced M1-related phenotypes and proinflammatory cytokine expression. In summary, our study highlighted DHA as one of future potential therapeutic options for the development of novel anticancer immunotherapies in lung cancer. 10.1016/j.intimp.2021.108427
    Study on the structure-activity relationship of dihydroartemisinin derivatives: Discovery, synthesis, and biological evaluation of dihydroartemisinin-bile acid conjugates as potential anticancer agents. Zou Xiaosu,Liu Chang,Li Congcong,Fu Rong,Xu Wei,Bian Hongzhu,Dong Xun,Zhao Xiaozhen,Xu Zhenye,Zhang Jinghua,Shen Zhengwu European journal of medicinal chemistry A series of dihydroartemisinin derivatives was synthesized, and their anti-proliferation activity against cancer cells was evaluated. Structure-activity relationship studies led to the discovery of dihydroartemisinin-bile acid conjugates that exhibit broad-spectrum anti-proliferation activities. Among them, the dihydroartemisinin-ursodeoxycholic acid conjugate (49) was the most potent, with IC values between 0.04 and 0.96 μM when tested to determine its inhibitory properties against 15 various cancer cell lines. In vivo experiments showed that compound 49 effectively suppressed tumor growth in an A549 cell xenograft model at the dosage of 10 mg/kg body weight and in Lewis lung cancer cell transplant model at the dosage of 12 mg/kg body weight. 10.1016/j.ejmech.2021.113754
    Dihydroartemisinin: A Potential Natural Anticancer Drug. Dai Xiaoshuo,Zhang Xiaoyan,Chen Wei,Chen Yihuan,Zhang Qiushuang,Mo Saijun,Lu Jing International journal of biological sciences Dihydroartemisinin (DHA) is an active metabolite of artemisinin and its derivatives (ARTs), and it is an effective clinical drug widely used to treat malaria. Recently, the anticancer activity of DHA has attracted increasing attention. Nevertheless, there is no systematic summary on the anticancer effects of DHA. Notably, studies have shown that DHA exerts anticancer effects through various molecular mechanisms, such as inhibiting proliferation, inducing apoptosis, inhibiting tumor metastasis and angiogenesis, promoting immune function, inducing autophagy and endoplasmic reticulum (ER) stress. In this review, we comprehensively summarized the latest progress regarding the anticancer activities of DHA in cancer. Importantly, the underlying anticancer molecular mechanisms and pharmacological effects of DHA and are the focus of our attention. Interestingly, new methods to improve the solubility and bioavailability of DHA are discussed, which greatly enhance its anticancer efficacy. Remarkably, DHA has synergistic anti-tumor effects with a variety of clinical drugs, and preclinical and clinical studies provide stronger evidence of its anticancer potential. Moreover, this article also gives suggestions for further research on the anticancer effects of DHA. Thus, we hope to provide a strong theoretical support for DHA as an anticancer drug. 10.7150/ijbs.50364
    Efficacy of Topically Administered Dihydroartemisinin in Treating Papillomavirus-Induced Anogenital Dysplasia in Preclinical Mouse Models. Viruses The artemisinin family of compounds is cytopathic in certain cancer cell lines that are positive for human papillomaviruses (HPV) and can potentially drive the regression of dysplastic lesions. We evaluated the efficacy of topical dihydroartemisinin (DHA) on cervical dysplasia and anal dysplasia in two papillomavirus mouse models: transgenic mice, which express HPV16 oncogenes; and immunodeficient NOD/SCID gamma (NSG) mice infected with papillomavirus (MmuPV1). Mice started treatment with DHA at 25 weeks of age () or 20 weeks post infection (MmuPV1-infected), when the majority of mice are known to have papillomavirus-induced low- to high-grade dysplasia. Mice were treated with or without topical DHA at the cervix or anus and with or without topical treatment with the chemical carcinogen 7,12 dimethylbenz(a)anthracene (DMBA) at the anus of in transgenic mice to induce neoplastic progression. Mice were monitored for overt tumor growth, and tissue was harvested after 20 weeks of treatment and scored for severity of histological disease. For MmuPV1-infected mice, anogenital lavages were taken to monitor for viral clearance. Tissues were also evaluated for viral gene expression at the RNA and/or protein levels. Treatment with topical DHA did not reduce dysplasia in the anogenital tract in either papillomavirus-induced mouse model and did not prevent progression to anal cancer in the DMBA-treated mice. 10.3390/v14081632
    Dihydroartemisinin loaded layered double hydroxide nanocomposites for tumor specific photothermal-chemodynamic therapy. Lu Jingsong,Guo Zhenhu,Che Shenglei,Gao Fei,Gu Zi,Xu Jianzhong,Chi Yongjie,Xu Wanling,Zhang Junxin,Takuya Nonaka,Yu Jing,Zhao Lingyun Journal of materials chemistry. B With the inspiration to develop new cancer nanotherapeutics by repurposing old drugs, in the current study, a novel two dimensional nanomedicine namely Mn doped, dihydroartemisinin (DHA) loaded layered double hydroxide (MnMgFe-LDH/DHA) with peroxide self-supplying properties for enhanced photothermal-chemodynamic therapy was proposed. Such nanostructures could be synthesized by a simple coprecipitation method, and the as-prepared MnMgFe-LDH/DHA exhibits excellent photothermal properties with a photothermal conversion efficiency up to 10.7%. Besides, the in situ reaction between the released DHA and Fe2+/Mn2+ produced by the degradation of LDH can lead to a burst of intracellular reactive oxygen species (ROS) by Fenton-like reactions. Furthermore, the in vivo experiments demonstrate that MnMgFe-LDH/DHA exhibits a remarkable chemodynamic/photothermal therapy (CDT/PTT) synergistic effect on tumor treatment with negligible damage to normal tissues. Finally, this research provides a smart strategy to construct a DHA repurposing nanomedicine for tumor specific treatment. 10.1039/d0tb01964j
    Evolution of resistance in vitro reveals mechanisms of artemisinin activity in . Rosenberg Alex,Luth Madeline R,Winzeler Elizabeth A,Behnke Michael,Sibley L David Proceedings of the National Academy of Sciences of the United States of America Artemisinins are effective against a variety of parasites and provide the first line of treatment for malaria. Laboratory studies have identified several mechanisms for artemisinin resistance in , including mutations in Kelch13 that are associated with delayed clearance in some clinical isolates, although other mechanisms are likely involved. To explore other potential mechanisms of resistance in parasites, we took advantage of the genetic tractability of , a related parasite that shows moderate sensitivity to artemisinin. Resistant populations of were selected by culture in increasing concentrations and whole-genome sequencing identified several nonconservative point mutations that emerged in the population and were fixed over time. Genome editing using CRISPR/Cas9 was used to introduce point mutations conferring amino acid changes in a serine protease homologous to DegP and a serine/threonine protein kinase of unknown function. Single and double mutations conferred a competitive advantage over wild-type parasites in the presence of drug, despite not changing EC values. Additionally, the evolved resistant lines showed dramatic amplification of the mitochondria genome, including genes encoding cytochrome and cytochrome oxidase I. Prior studies in yeast and mammalian tumor cells implicate the mitochondrion as a target of artemisinins, and treatment of wild-type parasites with high concentrations of drug decreased mitochondrial membrane potential, a phenotype that was stably altered in the resistant parasites. These findings extend the repertoire of mutations associated with artemisinin resistance and suggest that the mitochondrion may be an important target of inhibition of resistance in . 10.1073/pnas.1914732116
    Novel dihydroartemisinin dimer containing nitrogen atoms inhibits growth of endometrial cancer cells and may correlate with increasing intracellular peroxynitrite. Zhu Yan,Klausen Christian,Zhou Jieyun,Guo Xiangjie,Zhang Yu,Zhu Hua,Li Zhao,Cheng Jung-Chien,Xie Shuwu,Yang Wenjie,Li Ying,Leung Peter C K Scientific reports In the present study, a novel dimer, SM1044, selected from a series of dihydroartemisinin (DHA) derivatives containing nitrogen atoms comprising simple aliphatic amine linkers, showed strong growth inhibition in six types of human endometrial cancer (EC) cells, with half maximal inhibitory concentration (IC) and 95% confidence interval (CI) < 3.6 (1.16~11.23) μM. SM1044 evoked apoptosis and activated caspase-3, -8 and -9 in a concentration- and time-dependent manner, and these effects were manifested early in RL95-2 compared to KLE cells, possibly correlated with the induction of intracellular ONOO. Catalase and uric acid attenuated the growth inhibitory effects of SM1044 on EC cells, but sodium pyruvate did not. In vivo, the average xenograft tumour growth inhibition rates ranged from 35.8% to 49.9%, respectively, after 2.5 and 5.0 mg/kg SM1044 intraperitoneal treatment, and no obvious behavioural and histopathological abnormalities were observed in SM1044-treated mice in this context. SM1044 predominantly accumulated in the uteri of mice after a single injection. SM1044 displayed efficacy as a tumour suppressor with distinct mechanism of action and unique tissue distribution, properties that distinguish it from other artemisinin analogues. Our findings provide a new clue for artemisinin analogue against cancer. 10.1038/s41598-019-52108-6
    Chemical hybridization of sulfasalazine and dihydroartemisinin promotes brain tumor cell death. Ackermann Annemarie,Çapcı Aysun,Buchfelder Michael,Tsogoeva Svetlana B,Savaskan Nicolai Scientific reports Gliomas are primary brain tumors with still poor prognosis for the patients despite a combination of cytoreduction via surgery followed by a radio-chemotherapy. One strategy to find effective treatment is to combine two different compounds in one hybrid molecule via linker to add to or at best potentiate their impact on malignant cells. Here, we report on the effects of a newly synthesized hybrid of sulfasalazine (SAS) and dihydroartemisinin (DHA), called AC254. In previous studies, both SAS and DHA have already proved to have anti-tumor properties themselves and to have sensitizing respectively potentiating effects on other treatments against malignant tumors. We investigated the impact of individual drugs SAS and DHA, their 1:1 combination and a novel SAS-DHA hybrid compound (AC254) on rodent and human glioma cells. In our study SAS alone showed no or only a mild effect on glioma, whereas DHA led to a significant reduction of cell viability in a dose-dependent manner. Next we compared the efficacy of the hybrid AC254 to the combinational treatment of its parent compounds SAS and DHA. The hybrid was highly efficient in combating glioma cells compared to single treatment strategies regarding cell viability and cell death. Interestingly, AC254 showed a remarkable advantage over the combinational treatment with both parent compounds in most used concentrations. In addition to its reduction of tumor cell viability and induction of cell death, the hybrid AC254 displayed changes in cell cycle and reduction of cell migration. Taken together, these results demonstrate that clinically established compounds such as SAS and DHA can be potentiated in their anti-cancer effects by chemical hybridization. Thus, this concept provides the opportunity to devise new effective chemotherapeutic agents. 10.1038/s41598-021-99960-z
    Repurposing Artemisinin and its Derivatives as Anticancer Drugs: A Chance or Challenge? Ma Zhaowu,Woon Clariis Yi-Ning,Liu Chen-Guang,Cheng Jun-Ting,You Mingliang,Sethi Gautam,Wong Andrea Li-Ann,Ho Paul Chi-Lui,Zhang Daping,Ong Peishi,Wang Lingzhi,Goh Boon-Cher Frontiers in pharmacology Cancer has become a global health problem, accounting for one out of six deaths. Despite the recent advances in cancer therapy, there is still an ever-growing need for readily accessible new therapies. The process of drug discovery and development is arduous and takes many years, and while it is ongoing, the time for the current lead compounds to reach clinical trial phase is very long. Drug repurposing has recently gained significant attention as it expedites the process of discovering new entities for anticancer therapy. One such potential candidate is the antimalarial drug, artemisinin that has shown anticancer activities and . In this review, major molecular and cellular mechanisms underlying the anticancer effect of artemisinin and its derivatives are summarised. Furthermore, major mechanisms of action and some key signaling pathways of this group of compounds have been reviewed to explore potential targets that contribute to the proliferation and metastasis of tumor cells. Despite its established profile in malaria treatment, pharmacokinetic properties, anticancer potency, and current formulations that hinder the clinical translation of artemisinin as an anticancer agent, have been discussed. Finally, potential solutions or new strategies are identified to overcome the bottlenecks in repurposing artemisinin-type compounds as anticancer drugs. 10.3389/fphar.2021.828856
    Artemisinin inhibits angiogenesis by regulating p38 MAPK/CREB/TSP-1 signaling pathway in osteosarcoma. Li Zhi,Ding Xiaomin,Wu Haihui,Liu Chao Journal of cellular biochemistry Osteosarcoma is the most common bone tumor and characterizes a high metastatic potential. In osteosarcoma, angiogenesis is reported to be closely associated with tumor metastasis. Understanding the underlying mechanisms and accordingly developing therapeutic strategies are urgently desired. Antimalarial agent, artemisinin, has been reported to inhibit tumor angiogenesis. However, we still knew little about the effects of artemisinin on angiogenesis and its potential molecular mechanisms in human osteosarcoma. In this study, we found that artemisinin could induce both the expression and secretion of thrombospondin-1 (TSP-1) in a dose-dependent way in osteosarcoma cells. In addition, TSP-1 could effectively restore the artemisinin-induced suppression of angiogenesis in human umbilical vein endothelial cells (HUVECs). More importantly, we further found that phosphorylation of cAMP response element-binding protein (CREB) bond specifically to the promoter of TSP-1 and promoted its transcriptional activation. Moreover, our results showed that artemisinin could induce the phosphorylation of CREB via the activation of p38 mitogen-activated protein kinase (MAPK) signaling pathway in osteosarcoma cells. In vivo, we also found that artemisinin could inhibit osteosarcoma proliferation and angiogenesis by regulating the p38 MAPK/CREB/TSP-1 signaling pathway. Taken together, our findings indicated that artemisinin could inhibit angiogenesis by regulating the p38 MAPK/CREB/TSP-1 signaling pathway in osteosarcoma. 10.1002/jcb.28424
    Construction and anti-tumor activities of disulfide-linked docetaxel-dihydroartemisinin nanoconjugates. Li Ning,Guo Wenju,Li Yujie,Zuo Hengtong,Zhang Huihui,Wang Zhaoyun,Zhao Yongdan,Yang Fan,Ren Guolian,Zhang Shuqiu Colloids and surfaces. B, Biointerfaces Co-delivery of anti-tumor agents with outstanding stimulus-triggered drug release in tumor cells, especially with the aid of nanotechnology, provided the possibility to enhance delivery efficiency for targeting tumor cells and antitumor efficacy. In this paper, docetaxel-dihydroartemisinin nanoconjugates linked by disulfide bond were designed to increase co-delivery and anti-tumor efficacy. Docetaxel and dihydroartemisinin were synthesized using two-step reaction and furtherly assembled to nanoconjugates. Nanoprescription was optimized to evaluate its physicochemical properties. In vitro anti-tumor activities of nanoformulation were assessed by MTT. The flow cytometry was adopted to analyze cell apoptosis and cell cycle arrest. The wound healing assay was used to evaluate antimigratory-property. In vivo pharmacokinetic and pharmacodynamic studies were investigated in rats and 4T1 bearing Balb/c mice model after intravenous injection, respectively. The chemical structure of conjugate was confirmed. The prepared nanoparticles possessed uniform size distribution (172.10 ± 1.70 nm, PDI 0.05 ± 0.01), was stable during storage period, sustained release profiles and sensitive reduction responsiveness. MTT assay indicated that the toxicity of nanoconjugates was slightly weak. Flow cytometry studies showed that nanoconjugates could promote early apoptosis significantly and mainly arose from G/G phase. The wound healing assay provided an obvious antimetastatic potential of nanoparticles in 4T1 cells. The result of pharmacokinetic study suggested that nanoconjugates exhibited higher exposure levels. In vivo pharmacodynamic research showed that mice treated with docetaxel-dihydroartemisinin nanoconjugates had lower systemic toxicity and higher survival ratio than those of control groups. This potential of nanoconjugates was developed as a novel nanoplateform to treat tumor. 10.1016/j.colsurfb.2020.111018
    Pyrvinium pamoate can overcome artemisinin's resistance in anaplastic thyroid cancer. Li Yitian BMC complementary medicine and therapies BACKGROUND:Anaplastic thyroid carcinoma is a highly lethal subtype of thyroid cancer without effective therapies. Drug resistance in anaplastic thyroid carcinoma poses a significant problem. Although artemisinin exerts antitumor effects, but its efficacy in anaplastic thyroid carcinoma is unknown. METHODS:We used RNA sequencing to identify differentially expressed genes. Next, we determined the cause of ART resistance by testing the expression and activity of β-catenin, and enhanced ART activity with a WNT signaling inhibitor. RESULTS:Artemisinin suppressed the growth of BHT-101 but not human thyroid anaplastic carcinoma (CAL-62) cells. The mechanism of artemisinin resistance in CAL-62 was associated with the aberrant activation of WNT signaling. Pyrvinium pamoate, an inhibitor of WNT signaling, was used to overcome ART resistance in CAL-62 cells. The combination of artemisinin and pyrvinium pamoate suppressed the growth of CAL-62 cells and induced the apoptosis. CONCLUSIONS:Our study is the first to prove the efficacy of ART as monotherapy or in combination with PP in the management of anaplastic thyroid cancer, and that the inhibition of WNT signaling may overcome ART resistance. 10.1186/s12906-021-03332-z
    Development of GLUT1-targeting alkyl glucoside-modified dihydroartemisinin liposomes for cancer therapy. Shen Shuo,Du Maobo,Liu Qingbo,Gao Peng,Wang Jigang,Liu Shuzhi,Gu Liwei Nanoscale The antitumor activity of artemisinin derivatives has attracted much attention. However, lack of tumor targeting limits the anti-tumor activity of artemisinin derivatives. It is reported that tumor cells acquire energy through the glycolysis pathway. To meet their elevated glucose requirements, high expressions of glucose transporters (GLUTs) are observed in many malignant cells. On this basis, novel alkyl glycoside-modified dihydroartemisinin liposomes were successfully prepared with GLUT1 as the target and the glucose segment of an alkyl glycoside as the targeting head on the surface of liposomes. The particle size of the liposomes was 100.67 ± 1.25 nm, zeta potential was -22.93 ± 0.92 mV and encapsulation efficiency was 75.28 ± 0.73%, meanwhile the liposomes had good stability. In vitro targeting of liposomes was evaluated by fluorescence microscopy and flow cytometry. Compared with human L02 hepatocyte cells, the liposomes showed better targeting ability to human liver carcinoma cells HepG2 with the help of the glucose segment modified on the liposomes. In vivo targeting evaluation also showed that the tumor targeting of alkyl glycoside-modified liposomes was significantly improved, as well as the anti-tumor activity. These findings provide a research and theoretical basis for the development of artemisinin derivatives and other drug targeted antitumor nano-agents. 10.1039/d0nr05138a
    Suppression of asparagine synthetase enhances the antitumor potency of ART and artemalogue SOMCL-14-221 in non-small cell lung cancer. Xiao Ruoxuan,Ding Chunyong,Zhu Hongwen,Liu Xia,Gao Jing,Liu Qian,Lu Dayun,Zhang Naixia,Zhang Ao,Zhou Hu Cancer letters Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality. Artemisinin (ART) and SOMCL-14-221 (221), a spirobicyclic analogue of ART, have been reported to inhibit the proliferation of A549 cells with unclear underlying mechanism. In the present study, we validated that both ART and 221 inhibited the proliferation and migration of NSCLC cells and the growth of A549 xenograft tumors without appreciable toxicity. The proteomic data revealed proteins upregulated in ART and 221 groups were involved in "response to endoplasmic reticulum stress" and "amino acid metabolism". Asparagine synthetase (ASNS) was identified as a key node protein in these processes. Interestingly, knockdown of ASNS improved the antitumor potency of ART and 221 in vitro and in vivo, and treatments with ART and 221 disordered the amino acid metabolism of A549 cells. Moreover, ART and 221 activated ER stress, and inhibition of ER stress abolished the anti-proliferative effects of ART and 221. In conclusion, this study demonstrates that ART and 221 suppress tumor growth by triggering ER stress, and the inhibition of ASNS enhances the antitumor activity of ART and 221, which provides new strategy for drug combination therapy. 10.1016/j.canlet.2020.01.035
    Combination of dihydroartemisinin and resveratrol effectively inhibits cancer cell migration regulation of the DLC1/TCTP/Cdc42 pathway. Gao Junying,Ma Fengqiu,Wang Xingjie,Li Guorong Food & function Resveratrol (RES) is a polyphenolic plant antitoxin that increases the level of the tumor suppressor gene deleted in liver cancer 1 (DLC1) to suppress cancer progression. Dihydroartemisinin (DHA), a main active metabolite of anti-malarial drug artemisinin (ART), inhibits cancer cell invasion and migration by decreasing the translationally controlled tumor protein (TCTP), as reported in a few literature studies. Compelling evidence has shown that combination therapy with two or more compounds is more effective than treatment with a compound alone. However, the mechanism of combination of DHA and RES on inhibition of cancer cell migration has not been reported. In this study, our results showed that combination of DHA and RES, compared to each compound alone, synergistically inhibited migration along with the decrease of wound closures and F-actin formation in HepG2 and MDA-MB-231 cancer cells. This combination treatment up-regulated DLC1 and down-regulated TCTP expressions significantly. The two proteins were identified to colocalize in focal adhesions and form a complex. Depletion of DLC1 increased TCTP expression, and transfection with either GFP-DLC1-WT or GFP-DLC1-R718A (GAP-dead mutant) decreased the TCTP level markedly, indicating that DLC1 negatively regulated TCTP in a RhoGAP-independent manner. Furthermore, this combination treatment impeded the migration of HepG2 and MDA-MB-231 cancer cells via Cdc42 regulating JNK/NF-κB and N-WASP signaling pathways, and knockdown of DLC1 obviously increased the levels of Cdc42 and the molecules related to both signaling pathways in MDA-MB-231 cells. The combination also effectively inhibited the growth of xenograft tumors in an avian embryo model. In sum, we reveal a novel combination of DHA and RES that inhibits cancer cell migration by modulating the DLC1/TCTP axis to hinder the Cdc42 related signaling pathway. This combination treatment may be a promising therapeutic strategy to inhibit cancer cell migration by targeting DLC1 and TCTP. 10.1039/d0fo00996b
    Artemisinin reduces human melanoma cell migration by down-regulating alpha V beta 3 integrin and reducing metalloproteinase 2 production. Buommino Elisabetta,Baroni Adone,Canozo Nunzia,Petrazzuolo Marcella,Nicoletti Rosario,Vozza Antonio,Tufano Maria Antonietta Investigational new drugs Artemisinin and its derivatives are well known antimalarial drugs, particularly useful after resistance to traditional antimalarial pharmaceuticals has started to occur in Plasmodium falciparum. In recent years, anticancer activity of artemisinin has been reported both in vitro and in vivo. Artemisinin has inhibitory effects on cancer cell growth and anti-angiogenetic activity. In the present investigation, we analyzed the inhibitory effects of artemisinin on migratory ability of melanoma cell lines (A375P and A375M, low and medium metastatic properties, respectively). We demonstrate that artemisinin induces cell growth arrest in A375M, and affects A375P cells viability with cytotoxic and growth inhibitory effects, while it was not effective in contrasting proliferation of other tumor cell lines (MCF7 and MKN). In addition, artemisinin affected the migratory ability of A375M cells by reducing metalloproteinase 2 (MMP-2) production and down-regulating alpha v beta 3 integrin expression. These findings introduce a potential of artemisinin as a chemotherapeutic agent in melanoma treatment. 10.1007/s10637-008-9188-2
    Biodegradable iron-coordinated hollow polydopamine nanospheres for dihydroartemisinin delivery and selectively enhanced therapy in tumor cells. Dong Liang,Wang Chao,Zhen Wenyao,Jia Xiaodan,An Shangjie,Xu Zhiai,Zhang Wen,Jiang Xiue Journal of materials chemistry. B As the semisynthetic derivative and active metabolite of the effective anti-malarial drug artemisinin, dihydroartemisinin (DHA) has been investigated as an emerging therapeutic agent for tumor treatment based on the cytotoxicity of free-radicals originating from interactions with ferrous ions. Meanwhile, simultaneously delivering DHA and iron ions to tumors for selectively killing cancer cells is still a great challenge in DHA tumor therapy. Herein, we develop a facile yet efficient strategy based on iron-coordinated hollow polydopamine nanospheres to load DHA (DHA@HPDA-Fe). The as-prepared nanoagent is biodegradable and exhibits controllable release of DHA and Fe ions in tumor microenvironments, resulting in ferrous ion-enhanced production of cytotoxic reactive oxygen species (ROS) by DHA and thus effectively killing the tumor cells. In vivo therapy experiments indicated that the anti-tumor efficacy of DHA@HPDA-Fe was about 3.05 times greater than that of free DHA, and the tumor inhibition ratio was 88.7% compared with the control group, accompanied by negligible side effects, indicating that the proposed nanomedicine platform is promising for anti-tumor applications. 10.1039/c9tb01397k
    Dried leaf Artemisia annua efficacy against non-small cell lung cancer. Rassias Dina J,Weathers Pamela J Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer with poor prognosis. Artemisinin (AN), produced naturally in Artemisia annua L., has anti-cancer activity. Artemisinin delivered as dried leaf Artemisia (DLA) showed efficacy against malaria in rodents and humans. HYPOTHESIS/PURPOSE:DLA is posited as being at least as efficacious as artesunate (AS) in its ability to induce cytotoxicity in NSCLC cells and also inhibit tumor growth in a NSCLC xenograft murine model. STUDY DESIGN:Three NSCLC cell lines were used, a non-cancerous human fibroblast line, and xenograft murine models to compare efficacy of artemisinin delivered p.o. via DLA, DLA extracts (DLAe), and AS. METHODS:DLAe was compared to AS using NSCLC cell lines A549, H1299 and PC9 as well as non-cancerous human dermal fibroblasts (HDF) CCD-1108Sk line. Cell viability, cell migration and cell cycle were compared for AS and DLAe. Westerns measured activated caspases-3, -8 and -9 to determine involvement of intrinsic and/or extrinsic apoptotic pathways. Xenograft murine models of A549 and PC9 cells were used to measure tumor growth inhibition by AS or DLA, with tumor volume the primary endpoint. RESULTS:Both DLAe and AS suppressed A549, H1299 and PC9 cell viability with no inhibition of non-cancerous HDF CCD-1108Sk cells. Caspases-3, -8 and -9 were activated, suggesting cell death was stimulated through both intrinsic and/or extrinsic apoptotic pathways. Both drugs induced G2/M or mitotic arrest in PC9 and H1299 cells, and DLAe induced G1 arrest in A549 cells. AS and DLAe induced DNA damage as double stranded breaks evidenced by phosphorylation of histone H2AX. DLAe inhibited migration of PC9 and A549 cells. In A549 xenografted animals, p.o. AS and DLA inhibited relative tumor growth by 40% and 50%, respectively, compared to controls. AS was ineffective at inhibiting PC9-induced tumor growth, but DLA inhibited relative tumor growth by ∼50% compared to controls. CONCLUSION:This is the first study demonstrating efficacy of DLA and mechanistic differences of DLAe vs. AS, against NSCLC cells. Compared to AS, DLA possesses qualities of a novel therapeutic for patients with NSCLC. 10.1016/j.phymed.2018.09.167
    Artemisia annua L. extracts inhibit the in vitro replication of SARS-CoV-2 and two of its variants. Nair M S,Huang Y,Fidock D A,Polyak S J,Wagoner J,Towler M J,Weathers P J Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Artemisia annua L. has been used for millennia in Southeast Asia to treat "fever". Many infectious microbial and viral diseases have been shown to respond to A. annua and communities around the world use the plant as a medicinal tea, especially for treating malaria. AIM OF THE STUDY:SARS-CoV-2 (the cause of Covid-19) globally has infected and killed millions of people. Because of the broad-spectrum antiviral activity of artemisinin that includes blockade of SARS-CoV-1, we queried whether A. annua suppressed SARS-CoV-2. MATERIALS AND METHODS:Using Vero E6 and Calu-3 cells, we measured anti SARS-CoV-2 activity against fully infectious virus of dried leaf extracts of seven cultivars of A. annua sourced from four continents. IC50s were calculated and defined as the concentrations that inhibited viral replication by 50%; CC50s were also calculated and defined as the concentrations that kill 50% of cells. RESULTS:Hot-water leaf extracts based on artemisinin, total flavonoids, or dry leaf mass showed antiviral activity with IC values of 0.1-8.7 μM, 0.01-0.14 μg, and 23.4-57.4 μg, respectively. Antiviral efficacy did not correlate with artemisinin or total flavonoid contents of the extracts. One dried leaf sample was >12 years old, yet its hot-water extract was still found to be active. The UK and South African variants, B1.1.7 and B1.351, were similarly inhibited. While all hot water extracts were effective, concentrations of artemisinin and total flavonoids varied by nearly 100-fold in the extracts. Artemisinin alone showed an estimated IC of about 70 μM, and the clinically used artemisinin derivatives artesunate, artemether, and dihydroartemisinin were ineffective or cytotoxic at elevated micromolar concentrations. In contrast, the antimalarial drug amodiaquine had an IC = 5.8 μM. Extracts had minimal effects on infection of Vero E6 or Calu-3 cells by a reporter virus pseudotyped by the SARS-CoV-2 spike protein. There was no cytotoxicity within an order of magnitude above the antiviral IC values. CONCLUSIONS:A. annua extracts inhibit SARS-CoV-2 infection, and the active component(s) in the extracts is likely something besides artemisinin or a combination of components that block virus infection at a step downstream of virus entry. Further studies will determine in vivo efficacy to assess whether A. annua might provide a cost-effective therapeutic to treat SARS-CoV-2 infections. 10.1016/j.jep.2021.114016
    Farnesylthiosalicylic acid sensitizes hepatocarcinoma cells to artemisinin derivatives. Wu Liping,Pang Yilin,Qin Guiqi,Xi Gaina,Wu Shengnan,Wang Xiaoping,Chen Tongsheng PloS one Dihydroartemisinin (DHA) and artesunate (ARS), two artemisinin derivatives, have efficacious anticancer activities against human hepatocarcinoma (HCC) cells. This study aims to study the anticancer action of the combination treatment of DHA/ARS and farnesylthiosalicylic acid (FTS), a Ras inhibitor, in HCC cells (Huh-7 and HepG2 cell lines). FTS pretreatment significantly enhanced DHA/ARS-induced phosphatidylserine (PS) externalization, Bak/Bax activation, mitochondrial membrane depolarization, cytochrome c release, and caspase-8 and -9 activations, characteristics of the extrinsic and intrinsic apoptosis. Pretreatment with Z-IETD-FMK (caspase-8 inhibitor) potently prevented the cytotoxicity of the combination treatment of DHA/ARS and FTS, and pretreatment with Z-VAD-FMK (pan-caspase inhibitor) significantly inhibited the loss of ΔΨm induced by DHA/ARS treatment or the combination treatment of DHA/ARS and FTS in HCC cells. Furthermore, silencing Bak/Bax modestly but significantly inhibited the cytotoxicity of the combination treatment of DHA/ARS and FTS. Interestingly, pretreatment with an antioxidant N-Acetyle-Cysteine (NAC) significantly prevented the cytotoxicity of the combination treatment of DHA and FTS instead of the combination treatment of ARS and FTS, suggesting that reactive oxygen species (ROS) played a key role in the anticancer action of the combination treatment of DHA and FTS. Similar to FTS, DHA/ARS also significantly prevented Ras activation. Collectively, our data demonstrate that FTS potently sensitizes Huh-7 and HepG2 cells to artemisinin derivatives via accelerating the extrinsic and intrinsic apoptotic pathways. 10.1371/journal.pone.0171840
    Inhibition of autophagy by chloroquine potentiates synergistically anti-cancer property of artemisinin by promoting ROS dependent apoptosis. Ganguli Arnab,Choudhury Diptiman,Datta Satabdi,Bhattacharya Surela,Chakrabarti Gopal Biochimie Artemisinin (ART) is a well-known anti-malarial drug, and recently it is shown prospective to selectively kill cancer cells. But low potency makes it inappropriate for use as an anticancer drug. In this study, we modulated the ART-induced autophagy to increase Potency of ART as an anticancer agent. ART reduced the cell viability and colony forming ability of non-small lung carcinoma (A549) cells and it was non-toxic against normal lung (WI38) cells. ART induced autophagy at the early stage of treatment. Pre-treatment with chloroquine (CQ) and followed by ART treatment had synergistic combination index (CI) for cell death. Inhibition of autophagy by CQ pre-treatment led to accumulation of acidic vacuoles (AVOs) which acquainted with unprocessed damage mitochondria that subsequently promoted ROS generation, and resulted releases of Cyt C in cytosol that caused caspase-3 dependent apoptosis cell death in ART-treated A549 cells. Scavenging of ROS by antioxidant N-acetyl-cysteine (NAC) inhibited caspase-3 activity and rescued the cells from apoptosis. Similar effects were observed in other cancer cells SCC25 and MDA-MB-231. The appropriate manipulation of autophagy by using CQ provides a powerful strategy to increase the Potency of selective anticancer property of ART. 10.1016/j.biochi.2014.10.001
    pH-responsive artemisinin derivatives and lipid nanoparticle formulations inhibit growth of breast cancer cells in vitro and induce down-regulation of HER family members. Zhang Yitong J,Gallis Byron,Taya Michio,Wang Shusheng,Ho Rodney J Y,Sasaki Tomikazu PloS one Artemisinin (ART) dimers show potent anti-proliferative activities against breast cancer cells. To facilitate their clinical development, novel pH-responsive artemisinin dimers were synthesized for liposomal nanoparticle formulations. A new ART dimer was designed to become increasingly water-soluble as pH declines. The new artemisinin dimer piperazine derivatives (ADPs) remained tightly associated with liposomal nanoparticles (NPs) at neutral pH but were efficiently released at acidic pH's that are known to exist within solid tumors and organelles such as endosomes and lysosomes. ADPs incorporated into nanoparticles down regulated the anti-apoptotic protein, survivin, and cyclin D1 when incubated at low concentrations with breast cancer cell lines. We demonstrate for the first time, for any ART derivative, that ADP NPs can down regulate the oncogenic protein HER2, and its counterpart, HER3 in a HER2+ cell line. We also show that the wild type epidermal growth factor receptor (EGFR or HER1) declines in a triple negative breast cancer (TNBC) cell line in response to ADP NPs. The declines in these proteins are achieved at concentrations of NP109 at or below 1 µM. Furthermore, the new artemisinin derivatives showed improved cell-proliferation inhibition effects compared to known dimer derivatives. 10.1371/journal.pone.0059086
    Artemisinin derivative artesunate induces radiosensitivity in cervical cancer cells in vitro and in vivo. Luo Judong,Zhu Wei,Tang Yiting,Cao Han,Zhou Yuanyuan,Ji Rong,Zhou Xifa,Lu Zhongkai,Yang Hongying,Zhang Shuyu,Cao Jianping Radiation oncology (London, England) OBJECTIVE:Cervical cancer is the third most common type of cancer in women worldwide and radiotherapy remains its predominant therapeutic treatment. Artesunate (ART), a derivative of artemisinin, has shown radiosensitization effect in previous studies. However, such effects of ART have not yet been revealed for cervical cancer cells. METHODS:The effect of ART on radiosensitivity of human cervical cancer cell lines HeLa and SiHa was assessed using the clonogenic assay. Cell cycle progression and apoptosis alterations were analyzed by flow cytometry. For in vivo study, HeLa or SiHa cells were inoculated into nude mice to establish tumors. Tissues from xenografts were obtained to detect the changes of microvessel density, apoptosis and cell cycle distribution. Microarray was used to analyze differentially expressed genes. RESULTS:ART increased the radiosensitivity of HeLa cells (SER=1.43, P<0.001) but not of SiHa cells. Apoptosis and the G2-M phase transition induced by X-ray irradiation (IR) were enhanced by ART via increased Cyclin B1 expression in HeLa cells. Tumor growth of xenografts from HeLa but not SiHa cells was significantly inhibited by irradiation combined with ART (tumor volume reduction of 72.34% in IR+ART group vs. 41.22% in IR group in HeLa cells and 48.79% in IR+ART group vs. 44.03% in IR alone group in SiHa cells). Compared with the irradiated group, cell apoptosis was increased and the G2/M cell cycle arrest was enhanced in the group receiving irradiation combined with ART. Furthermore, compared with radiation alone, X-ray irradiation plus ART affected the expression of 203 genes that function in multiple pathways including RNA transport, the spliceosome, RNA degradation and p53 signaling. CONCLUSION:ART potently abrogates the G2 checkpoint control in HeLa cells. ART can induce radiosensitivity of HeLa cells in vitro and in vivo. 10.1186/1748-717X-9-84
    Enhanced delivery of artemisinin and its analogues to cancer cells by their adducts with human serum transferrin. Yang Yan,Zhang Xiaomin,Wang Xiaofen,Zhao Xiaomei,Ren Tianrui,Wang Feng,Yu Bo International journal of pharmaceutics Artemisinin (ART) and its analogues, such as dihydroartesunate (DHA) and artesunate (ATS), are sesquiterpene lactones with anticancer activities. Transferrin (Tf) receptor is frequently overexpressed in cancer cells. In order to improve the delivery and the anticancer activity of ART and its analogues, adducts of Tf with ART, DHA or ATS were fabricated by simply combining ART, DHA or ATS with Tf. Increased antitumor effects of these adducts were observed on human liver hepatocellular carcinoma (HepG2) and lung adenocarcinoma (A549) cells. Meanwhile, only a low level of toxic effect was observed on normal human liver cells (HL-7702). Improved cellular uptake of ATS-Tf adduct compared to ATS alone was confirmed by HPLC analysis. UV-vis, fluorescence spectroscopy and docking study further confirmed the formation of the adducts with relatively high binding constants at neutral pH (7.4×10(4), 4.2×10(5) and 3.4×10(5)M(-1), for ART-Tf, DHA-Tf and ATS-Tf, respectively, at pH 7.4). However, the adducts became less stable with reduced binding constants under an acidic condition (2.6×10(4), 1.9×10(4) and 1.7×10(4)M(-1), for ART-Tf, DHA-Tf and ATS-Tf, respectively, at pH 5.5). A possible mechanism of the anticancer effect by these adducts was proposed. The short term and long term stability of ART-Tf in the presence of human serum albumin (HSA) was also studied. Our results showed that adducts of ART and its analogues with Tf, especially ATS-Tf and DHA-Tf, have significant anticancer effects to cancer cells, with minimal side effects on normal cells, therefore, are promising as potential novel anticancer agents. 10.1016/j.ijpharm.2014.03.044
    Induction of autophagy and autophagy-dependent apoptosis in diffuse large B-cell lymphoma by a new antimalarial artemisinin derivative, SM1044. Cheng Chunyan,Wang Tao,Song Zhiqun,Peng Lijun,Gao Mengqing,Hermine Olivier,Rousseaux Sophie,Khochbin Saadi,Mi Jian-Qing,Wang Jin Cancer medicine Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma. R-CHOP is currently the standard therapy for DLBCL, but the prognosis of refractory or recurrent patients remains poor. In this study, we synthesized a new water-soluble antimalarial drug artemisinin derivative, SM1044. The treatment of DLBCL cell lines with SM1044 induces autophagy-dependent apoptosis, which is directed by an accelerated degradation of the antiapoptosis protein Survivin, via its acetylation-dependent interaction with the autophagy-related protein LC3-II. Additionally, SM1044 also stimulates the de novo synthesis of ceramide, which in turn activates the CaMKK2-AMPK-ULK1 axis, leading to the initiation of autophagy. Our findings not only elucidate the mechanism of autophagy-dependent apoptosis in DLBCL cells, but also suggest that SM1044 is a promising therapeutic molecule for the treatment of DLBCL, along with R-CHOP regimen. 10.1002/cam4.1276
    Cytotoxic effect of artemisinin and its derivatives on human osteosarcoma cell lines. Jirangkul Puripun,Srisawat Phutsapong,Punyaratabandhu Thippachart,Songpattanaslip Thawee,Mungthin Mathirut Journal of the Medical Association of Thailand = Chotmaihet thangphaet BACKGROUND:Osteosarcoma is the most common, non-hematopoietic, primary bone cancer Current standard treatment is to use neoadjuvant chemotherapy followed by surgical resection. However many complications from chemotherapy have been reported. Some studies have reported artemisinin derivatives showed cytotoxic and anti-angiogenic properties. OBJECTIVE:To investigate cytotoxic properties ofartemisinin and its derivatives on human osteosarcoma cell lines. MATERIAL AND METHOD:Osteosarcoma cell lines (MG63 and 148B) were continuously cultured. MTT assay was used to evaluate cytotoxic properties ofartemisinin derivatives at 48 hours of incubation. These cell lines were also tested against doxorubicin as a control. Each IC50 value represented the mean ofat least 3 experiments. Independent t-test was used to test differences between groups. RESULTS:Artemisinin and its derivatives at micromolar range exhibited anti-cancer growth activities in human osteosarcoma cell lines. Among them, RKA182 the new synthetic tetraoxane is the most effective in inhibiting cell growth. In addition, water-soluble properties ofdrugs may be the main factor in cytotoxicity. CONCLUSION:The promising result shows that artemisinin and its derivative inhibits the growth of human osteosarcoma cells. This study indicated that RKA182 may be apotent andpromising agent to combat osteosarcoma. Further studies should be conducted of new synthetic drugs as possible anti-cancer drugs or adjuvant therapy in the clinical treatment of osteosarcoma.
    Artemisinin and its derivatives: a potential treatment for leukemia. Lam Nelson Siukei,Long Xinxin,Wong Jonathan W,Griffin Robert C,Doery James C G Anti-cancer drugs Artemisinin (ART) and its derivatives are one of the most important classes of antimalarial agents, originally derived from a Chinese medicinal plant called Artemisia annua L. Beyond their outstanding antimalarial and antischistosomal activities, ART and its derivatives also possess both in-vitro and in-vivo activities against various types of cancer. Their anticancer effects range from initiation of apoptotic cell death to inhibition of cancer proliferation, metastasis and angiogenesis, and even modulation of the cell signal transduction pathway. This review provides a comprehensive update on ART and its derivatives, their mechanisms of action, and their synergistic effects with other chemicals in targeting leukemia cells. Combined with limited evidence of drug resistance and low toxicity profile, we conclude that ART and its derivatives, including dimers, trimers, and hybrids, might be a potential therapeutic alternative to current chemotherapies in combating leukemia, although more studies are necessary before they can be applied clinically. 10.1097/CAD.0000000000000697
    Artemisinin Ameliorates Osteoarthritis by Inhibiting the Wnt/β-Catenin Signaling Pathway. Zhong Gang,Liang Ruiming,Yao Jun,Li Jia,Jiang Tongmeng,Liu Jianwei,Le Yiguan,Shen Chong,Long Huiping,Lu Huiping,Ma Shiting,Luo Jun,Miao Zhikang,Su Wei,Zheng Li,Zhao Jinmin Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology BACKGROUND/AIMS:Current drug therapies for osteoarthritis (OA) are not practical because of the cytotoxicity and severe side-effects associated with most of them. Artemisinin (ART), an antimalarial agent, is well known for its safety and selectivity to kill injured cells. Based on its anti-inflammatory activity and role in the inhibition of OA-associated Wnt/β-catenin signaling pathway, which is crucial in the pathogenesis of OA, we hypothesized that ART might have an effect on OA. METHODS:The chondro-protective and antiarthritic effects of ART on interleukin-1-beta (IL-1β)-induced and OA patient-derived chondrocytes were investigated in vitro using cell viability assay, glycosaminoglycan secretion, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, and western blotting. We also used OA model rats constructed by anterior cruciate ligament transection and medial meniscus resection (ACLT+MMx) in the joints to investigate the effects of ART on OA by gross observation, morphological staining, immunohistochemistry, and enzyme-linked immunosorbent assay. RESULTS:ART exhibited potent anti-inflammatory effects by inhibiting the expression of proinflammatory chemokines and cytokines, including interleukin (IL)-1β, IL-6, tumor necrosis factor alpha, and matrix metallopeptidase-13. It also showed favorable chondro-protective effect as evidenced by enhanced cell proliferation and viability, increased glycosaminoglycan deposition, prevention of chondrocyte apoptosis, and degeneration of cartilage. Further, ART inhibited OA progression and cartilage degradation via the Wnt/β-catenin signaling pathway, suggesting that it might serve as a Wnt/β-catenin antagonist to reduce inflammation and prevent cartilage degradation. CONCLUSION:In conclusion, ART alleviates IL-1β-mediated inflammatory response and OA progression by regulating the Wnt/β-catenin signaling pathway. Thereby, it might be developed as a potential therapeutic agent for OA. 10.1159/000495926
    Treatment of Multidrug-Resistant Leukemia Cells by Novel Artemisinin-, Egonol-, and Thymoquinone-Derived Hybrid Compounds. Gruber Lisa,Abdelfatah Sara,Fröhlich Tony,Reiter Christoph,Klein Volker,Tsogoeva Svetlana B,Efferth Thomas Molecules (Basel, Switzerland) Two major obstacles for successful cancer treatment are the toxicity of cytostatics and the development of drug resistance in cancer cells during chemotherapy. Acquired or intrinsic drug resistance is responsible for almost 90% of treatment failure. For this reason, there is an urgent need for new anticancer drugs with improved efficacy against cancer cells, and with less toxicity on normal cells. There are impressive examples demonstrating the success of natural plant compounds to fight cancer, such as alkaloids, taxanes, and anthracyclines. Artesunic acid (ARTA), a drug for malaria treatment, also exerts cytotoxic activity towards cancer cells. Multidrug resistance often results from drug efflux pumps (ABC-transporters) that reduce intracellular drug levels. Hence, it would be interesting to know, whether ARTA could overcome drug resistance of tumor cells, and in what way ABC-transporters are involved. Different derivatives showing improved features concerning cytotoxicity and pharmacokinetic behavior have been developed. Considering both drug sensitivity and resistance, we chose a sensitive and a doxorubicin-resistant leukemia cell line and determined the killing effect of ARTA on these cells. Molecular docking and doxorubicin efflux assays were performed to investigate the interaction of the derivatives with -glycoprotein. Using single-cell gel electrophoresis (alkaline comet assay), we showed that the derivatives of ARTA induce DNA breakage and accordingly programmed cell death, which represents a promising strategy in cancer treatment. ARTA activated apoptosis in cancer cells by the iron-mediated generation of reactive oxygen species (ROS). In conclusion, ARTA derivatives may bear the potential to be further developed as anticancer drugs. 10.3390/molecules23040841
    A novel derivative of artemisinin inhibits cell proliferation and metastasis via down-regulation of cathepsin K in breast cancer. Gu Xiangyu,Peng Yayuan,Zhao Yuyu,Liang Xin,Tang Yun,Liu Jianwen European journal of pharmacology Breast cancer is one of the main diagnosis cancers annually worldwide. It is difficult to thorough cure due to drug resistance and the high possibility of metastasis. SM934 is a novel water-soluble artemisinin analog, and has been reported to have a promising therapeutic effect on multiple autoimmune diseases. In this study, SM934 was combined with Testosterone, which is related to prostate cancer, and the reaction product was SM934-Testosterone. We aimed to explore whether SM934, Testosterone and SM934-Testosterone could inhibit tumorigenesis and metastasis of breast cancer cells. Moreover, the mechanism also remains to be clarified. The results of our study showed that among the three compounds, only SM934-Testosterone treatment could lead to the suppression of cell proliferation and metastasis with IC = 30.66 ± 2.13 μM at 24 h in MDA-MB-231 and IC = 31.11 ± 1.79 μM at 24 h in SK-BR-3, where apoptosis was induced. But SM934-Testosterone showed little effects on breast cancer in vivo due to its poor water-solubility. Furthermore, computational target prediction and experimental validation demonstrated that Cathepsin K was the target of SM934-Testosterone. SM934-Testosterone inhibited the expression of Cathepsin K in breast cancer cells. Then, down-regulation of Cathepsin K in cancer cells by transfected with Cathepsin K shRNA inhibited cell proliferation and metastasis of breast cancer cells. Moreover, pathway enrichment was performed to understand the mechanism of action that Cathepsin K could adjust apoptosis regulator Bcl-X, and knockdown of Cathepsin K by SM934-Testosterone resulted in the reduction of Bcl-xL, which has been reported to be related to the proliferation and metastasis of cells. Collectively, SM934-Testosterone inhibited proliferation and metastasis ability of breast cancer cells via inhibiting the expression of Cathepsin K followed by the inhibition of Bcl-xL. 10.1016/j.ejphar.2019.05.011
    Artemisinin Mediates Its Tumor-Suppressive Activity in Hepatocellular Carcinoma Through Targeted Inhibition of FoxM1. Nandi Deeptashree,Cheema Pradeep Singh,Singal Aakriti,Bharti Hina,Nag Alo Frontiers in oncology The aberrant up-regulation of the oncogenic transcription factor Forkhead box M1 (FoxM1) is associated with tumor development, progression and metastasis in a myriad of carcinomas, thus establishing it as an attractive target for anticancer drug development. FoxM1 overexpression in hepatocellular carcinoma is reflective of tumor aggressiveness and recurrence, poor prognosis and low survival in patients. In our study, we have identified the antimalarial natural product, Artemisinin, to efficiently curb FoxM1 expression and activity in hepatic cancer cells, thereby exhibiting potential anticancer efficacy. Here, we demonstrated that Artemisinin considerably mitigates FoxM1 transcriptional activity by disrupting its interaction with the promoter region of its downstream targets, thereby suppressing the expression of numerous oncogenic drivers. Augmented level of FoxM1 is implicated in drug resistance of cancer cells, including hepatic tumor cells. Notably, FoxM1 overexpression rendered HCC cells poorly responsive to Artemisinin-mediated cytotoxicity while FoxM1 depletion in resistant liver cancer cells sensitized them to Artemisinin treatment, manifested in lower proliferative and growth index, drop in invasive potential and repressed expression of EMT markers with a concomitantly increased apoptosis. Moreover, Artemisinin, when used in combination with Thiostrepton, an established FoxM1 inhibitor, markedly reduced anchorage-independent growth and displayed more pronounced death in liver cancer cells. We found this effect to be evident even in the resistant HCC cells, thereby putting forth a novel combination therapy for resistant cancer patients. Altogether, our findings provide insight into the pivotal involvement of FoxM1 in the tumor suppressive activities of Artemisinin and shed light on the potential application of Artemisinin for improved therapeutic response, especially in resistant hepatic malignancies. Considering that Artemisinin compounds are in current clinical use with favorable safety profiles, the results from our study will potentiate its utility in juxtaposition with established FoxM1 inhibitors, promoting maximal therapeutic efficacy with minimal adverse effects in liver cancer patients. 10.3389/fonc.2021.751271
    Development of artemisinin compounds for cancer treatment. Lai Henry C,Singh Narendra P,Sasaki Tomikazu Investigational new drugs Artemisinin contains an endoperoxide moiety that can react with iron to form cytotoxic free radicals. Cancer cells contain significantly more intracellular free iron than normal cells and it has been shown that artemisinin and its analogs selectively cause apoptosis in many cancer cell lines. In addition, artemisinin compounds have been shown to have anti-angiogenic, anti-inflammatory, anti-metastasis, and growth inhibition effects. These properties make artemisinin compounds attractive cancer chemotherapeutic drug candidates. However, simple artemisinin analogs are less potent than traditional cancer chemotherapeutic agents and have short plasma half-lives, and would require high dosage and frequent administration to be effective for cancer treatment. More potent and target-selective artemisinin-compounds are being developed. These include artemisinin dimers and trimers, artemisinin hybrid compounds, and tagging of artemisinin compounds to molecules that are involved in the intracellular iron-delivery mechanism. These compounds are promising potent anticancer compounds that produce significantly less side effect than traditional chemotherapeutic agents. 10.1007/s10637-012-9873-z
    Development of artesunate intelligent prodrug liposomes based on mitochondrial targeting strategy. Journal of nanobiotechnology Breast cancer is the leading cause of cancer-related deaths in women and remains a formidable therapeutic challenge. Mitochondria participate in a myriad of essential cellular processes, such as metabolism, and are becoming an ideal target for cancer therapy. Artemisinin and its derivatives have demonstrated multiple activities in the context of various cancers. Mitochondrial autophagy(mitophagy) is one of the important anti-tumor mechanisms of artemisinin drugs. However, the lack of specific tumor targeting ability limits the anti-tumor efficacy of artemisinin drugs. In this study, a GSH-sensitive artesunate smart conjugate (TPP-SS-ATS) was synthesized and liposomes (TPP-SS-ATS-LS) that target tumor cells and mitochondria were further prepared. The advantages of TPP-SS-ATS-LS targeting to the breast tumor were verified by in vivo and in vitro evaluations. In our study, the cytotoxicity was obviously enhanced in vitro and tumor growth inhibition rate was increased from 37.7% to 56.4% at equivalent artesunate dosage in breast cancer orthotopic implanted mice. Meanwhile, mitochondrial dysfunction, suppression of ATP production and respiratory capacity were detected in breast cancer cells. We further discovered that TPP-SS-ATS-LS inhibited tumor cells proliferation through mitophagy by regulating PHB2 and PINK1 expression These results provide new research strategies for the development of new artemisinin-based anti-tumor drugs. 10.1186/s12951-022-01569-5
    Antineoplastic activity of artemisinin in adrenocortical carcinoma. Lorini Luigi,Grisanti Salvatore,Ambrosini Roberta,Cosentini Deborah,Laganà Marta,Grazioli Luigi,Tiberio Guido A M,Sigala Sandra,Berruti Alfredo Endocrine 10.1007/s12020-019-02077-7
    Design, synthesis and biological evaluation of artemisinin derivatives containing fluorine atoms as anticancer agents. Li Shu,Li Gongming,Yang Xiaohong,Meng Qian,Yuan Shuo,He Yun,Sun Dequn Bioorganic & medicinal chemistry letters Ten novel artemisinin derivatives containing fluorine atoms were synthesized and their structures were confirmed by H NMR, C NMR and HRMS technologies in this study. The in vitro cytotoxicity against U87MG, SH-SY5Y, MCF-7, MDA-MB-231, A549 and A375 cancer cell lines was evaluated by MTT assay. Compound 9j was the most potent anti-proliferative agent against the human breast cancer MCF-7 cells (IC = 2.1 μM). The mechanism of action of compound 9j was further investigated by analysis of cell apoptosis and cell cycle. Compound 9j induced cell apoptosis and arrested cell cycle at G1 phase in MCF-7 cells. Our promising findings indicated that the compound 9j could stand as potential lead compound for further investigation. 10.1016/j.bmcl.2018.05.035
    Antinociception induced by artemisinin nanocapsule in a model of postoperative pain via spinal TLR4 inhibition. Elisei L M S,Moraes T R,Malta I H,Charlie-Silva I,Sousa I M O,Veras F P,Foglio M A,Fraceto L F,Galdino G Inflammopharmacology Artemisinin (ART) was initially described for the control of inflammation and pain. However, the mechanisms involved with its antinociceptive effect are still poorly understood. Thus, this present study aimed to investigate the effect of ART in both free and nanocapsulated form on postoperative pain, as well as the participation of the spinal Toll-like receptor 4 (TLR4) in this process. Postoperative pain was induced using the skin/muscle incision retraction (SMIR) model in male Swiss mice. After 3 and 28 days of SMIR, the animals received an intrathecal injection of free or nanocapsulated ART, and the nociceptive threshold was evaluated by von Frey filament test. To evaluate the involvement of the microglia, astrocytes, and TLR4, minocycline (a microglia inhibitor), fluorocitrate (an astrocyte inhibitor), and Lipopolysaccharide Rhodobacter sphaeroides (LPS-RS), a TLR4 antagonist, were intrathecally injected on the third day of SMIR. The levels of spinal TLR4 protein and proinflammatory cytokines tumor necrosis factor-alpha (TNF-α), and interleukin-1-beta (IL-1β) were quantified by western blot and enzyme-linked immunosorbent assay, respectively. The results showed that free ART reduced postoperative pain (P < 0.001, F = 7.49, 16.66% for 1000 ng dose; and P < 0.01, F = 7.49, 14.58% for 500 ng dose) on the 3rd day of SMIR; while the ART nanocapsule had this effect on both the third (P < 0.001; F = 4.94; 43.75, 39.58 and 72.91% for the 250, 500 and 1000 ng doses, respectively) and 28th (P < 0.05; F = 7.71; 29.16 and 33.33% for the 500 and 1000 ng doses, respectively) day. The ART nanocapsule had a more potent and longer antinociceptive effect than free ART or morphine. Postoperative pain was also reduced by minocycline and LPS-RS. The ART nanocapsule also reduced the increased levels of TLR4, TNF-α, and IL-1β induced by SMIR. These data suggest that the ART nanocapsule has a potent analgesic effect on postoperative pain at the spinal level, and this response involves the inhibition of TLR4 and the proinflammatory cytokines TNF-α and IL-1β. 10.1007/s10787-020-00756-w
    Artemisinin inhibits neuroblastoma proliferation through activation of AHP-activated protein kinase (AMPK) signaling. Tan Wei-Qiang,Chen Gang,Jia Bing,Ye Ming Die Pharmazie Recent population studies suggest that the use of artemisinin is associated with reduced incidence and improved prognosis of certain cancers. In the current study, we assessed the effect of artemisinin on neuroblastoma cells using SHSY5Y cells. We found that artemisinin inhibited growth and modulated expression of cell-cycle regulators in these cells. Treatment with artemisinin was also associated with activation of AMP kinase and inhibition of mTOR/p70S6K/pS6 signaling in SHSY5Y cells. In addition, inhibition of AMPK signaling reversed impact on the anti-proliferative roles of artemisinin. Taken together, these results provide evidence for a mechanism that may contribute to the antineoplastic effects of artemisinin suggested by recent population studies and justify further work to explore its potential roles in neuroblastoma prevention and treatment.
    Synthesis and cytotoxicity of novel artemisinin derivatives containing sulfur atoms. Xu Cang-Cang,Wu Juan-Juan,Xu Tao,Yao Chun-Hua,Yu Bo-Yang,Liu Ji-Hua European journal of medicinal chemistry Ten novel artemisinin derivatives containing sulfur atoms were designed and synthesized and their structures were confirmed by (1)H NMR, (13)C NMR and HRMS technologies in this study. All compounds were reported for the first time. The in vitro cytotoxicity against PC-3, SGC-7901, A549 and MDA-MB-435s cancer cell lines was evaluated by MTT assay. Compounds 4a and 4f displayed potent antitumor activity against PC-3, SGC-7901 and A549 cells with IC50 ranging from 1.6 to 30.5 μM, which values are compared to that of 5-FU (IC50 from 6.8 to 42.5 μM). Compounds 4a and 4f showed high specificity towards human lung cancer A549 cells compared to normal human hepatic L-02 cells with selectivity index of 16.1 and 50.1 respectively. Our promising findings indicated that the compounds 4a and 4f could stand as potential lead compounds for further investigation. 10.1016/j.ejmech.2016.08.015
    Artemisinin inhibits breast cancer-induced osteolysis by inhibiting osteoclast formation and breast cancer cell proliferation. Li Jia,Feng Wenyu,Lu Huiping,Wei Yan,Ma Shiting,Wei Linfeng,Liu Qian,Zhao Jinmin,Wei Qingjun,Yao Jun Journal of cellular physiology In addition to being used to treat malaria, artemisinin (Art) can be used as an anti-inflammatory and antitumor agent. In this study, we evaluated the effects of Art on osteoclast formation and activation and on the development of breast cancer cells in bone. To evaluate the effect of Art on osteoclast differentiation in vitro, we treated bone marrow-derived macrophages (BMMs) with various concentrations of Art and evaluated the expression of genes and proteins involved in osteoclast formation. We also performed cell counting kit-8 assays to evaluate the toxicity of Art in BMMs and MDA-MB-231 cells. We also performed Transwell assays, wound-healing assays, colony formation assays, and cell apoptosis assays to evaluate the effect of Art in MDA-MB-231 cells. We also evaluated the effect of Art in an in vivo osteoclast bone resorption assay using a nude mouse model. We demonstrated that Art inhibits the differentiation and establishment of osteoclasts even though Art is not toxic to osteoclasts. In addition, Art reduced expression of genes involved in osteoclast formation and inhibited osteoclast bone resorption in a concentration-dependent manner. Based on our data, we believe that Art can inhibit proliferation of breast cancer cells by activating apoptosis pathways, and inhibit osteoclast formation and differentiation by inhibiting activation of cathepsin K, ATPase H+ transporting V0 subunit D2, nuclear factor of activated T cells 1, calcitonin receptor, and tartrate-resistant acid phosphatase and by inhibiting nuclear factor-κB activation. 10.1002/jcp.27875
    A survey on anticancer effects of artemisinin, iron, miconazole, and butyric acid on 5637 (bladder cancer) and 4T1 (Breast cancer) cell lines. Shahbazfar Amir Ali,Zare Payman,Ranjbaran Mehrdad,Tayefi-Nasrabadi Hossein,Fakhri Omid,Farshi Yashar,Shadi Sahar,Khoshkerdar Afsaneh Journal of cancer research and therapeutics CONTEXT:Anticancer properties of artemisinin and its derivatives have been shown in many experiments. AIMS:Addition of butyric acid, miconazole, and iron to this traditional drug has been done in order to enhance its anticancer potency. MATERIALS AND METHODS:Cell lines 5637 and 4T1, were cultivated and classified into 13 groups of three each. Different doses of artemisinin with constant doses of iron, miconazole and butyric acid, were added to the cultures. At the end of exposure pathological and enzymatic studies were performed. RESULTS:In four groups treated with different doses of artemisinin and iron, dose-dependent changes were observed. These changes included apoptosis and necrosis with dominance of apoptosis. The supernatant lactate dehydrogenase (LDH) level was increased in a dose-dependent manner, but there was no significant increase in the cell fraction of malonyldialdehyde (MDA) or LDH. In four other groups, which received miconazole, butyric acid and iron in addition to different doses of artemisinin, necrosis was more prominent than apoptosis, and the MDA level did not show any significant change, but LDH was increased. The groups treated with miconazole showed identical changes, with less severity compared to combination therapy groups. In butyric acid-treated groups, the only detectable changes were, mild cell swelling, few apoptosis, and rare necrosis. CONCLUSIONS:A combination therapy with artemisinin can be more effective against cancer cells than monotherapy with that. Butyric acid was not effective on cancer cells. Miconazole deviated the nature of cell death from apoptosis to necrosis and it must be used under caution. 10.4103/0973-1482.137975
    Anticancer Activity of Artemisinin and its Derivatives. Slezakova Silvia,Ruda-Kucerova Jana Anticancer research Artemisinin is an extract from the plant Artemisia annua. With its semi-synthetic derivatives, they form a group of well-known and efficacious antimalarial drugs. Recent studies have documented the potential anticancer effect of artemisinin and its derivatives (ARTs). This review summarizes results of preclinical studies, documenting mechanisms of anticancer actions of ARTs and clinical studies focused mainly on efficacy, safety and dose-ranging of ARTs as anticancer chemotherapeutics. The main mechanisms of action of ARTs is the production of reactive oxygen species, inhibition of cell cycle in G/G phase, induction of apoptosis and inhibition of angiogenesis. Safety studies have shown no evident toxicity and low incidence of adverse effects. ARTs potential to inhibit growth of solid tumours suggests their application in a neoadjuvant therapy. Dihydroartemisinin and artesunate exhibit chemosensitising effects in vivo in breast, lung, pancreas and glioma cancer cells, proposing the use of ARTs also in combination anticancer therapy. 10.21873/anticanres.12046
    Artemisinin and Its Derivatives as a Repurposing Anticancer Agent: What Else Do We Need to Do? Li Zhe,Li Qin,Wu Jun,Wang Manyuan,Yu Junxian Molecules (Basel, Switzerland) Preclinical investigation and clinical experience have provided evidence on the potential anticancer effect of artemisinin and its derivatives (ARTs) in the recent two decades. The major mechanisms of action of ARTs may be due to toxic-free radicals generated by an endoperoxide moiety, cell cycle arrest, induction of apoptosis, and inhibition of tumor angiogenesis. It is very promising that ARTs are expected to be a new class of antitumor drugs of wide spectrum due to their detailed information regarding efficacy and safety. For developing repurposed drugs, many other characteristics of ARTs should be studied, including through further investigations on possible new pathways of anticancer effects, exploration on efficient and specific drug delivery systems-especially crossing biological barriers, and obtaining sufficient data in clinical trials. The aim of this review is to highlight these achievements and propose the potential strategies to develop ARTs as a new class of cancer therapeutic agents. 10.3390/molecules21101331
    Enhancement of cytotoxicity of artemisinin toward cancer cells by transferrin-mediated carbon nanotubes nanoparticles. Zhang Huijuan,Ji Yandan,Chen Qianqian,Jiao Xiaojing,Hou Lin,Zhu Xiali,Zhang Zhenzhong Journal of drug targeting Artemisinin (ART) is a kind of drug with an endoperoxide bridge which tends to react with Fe(2+) to generate radicals for killing cancer cells. However, simultaneous delivery of hydrophobic ART and Fe(2+) ions into cancer cells remains a major challenge. In this study, a multi-functional tumor-targeting drug delivery system employing hyaluronic acid-derivatized multi-walled carbon nanotubes (HA-MWCNTs) as drug carriers, transferrin (Tf) as targeting ligand and ART as a model drug for cancer treatment was constructed. This delivery system (HA-MWCNTs/Tf@ART) not only retained optical property of MWCNTs and cytotoxicity of ART but also demonstrated synergistic anti-tumor effect using ART and Tf. Compared with free ART, remarkably enhanced anti-tumor efficacy of this drug vehicle was realized both in cultured MCF-7 cells in vitro and in a tumor-bearing murine model in vivo, due to increased intracellular accumulation of ART and co-delivery of Tf and ART analogs. HA-MWCNTs/Tf@ART with laser irradiation demonstrated the highest inhibition effect compared to the other groups. This result may provide a new way of using promising natural drugs for cancer therapy. 10.3109/1061186X.2015.1016437
    Artemisinin-Daumone Hybrid Inhibits Cancer Cell-Mediated Osteolysis by Targeting Cancer Cells and Osteoclasts. Ma Gwang Taek,Lee Sun Kyoung,Park Kwang-Kyun,Park Junhee,Son Seung Hwa,Jung Mankil,Chung Won-Yoon Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology BACKGROUND/AIMS:Bone metastasis of cancer cells decreases patient survival and quality of life. Hybridization via the covalent coupling of two bioactive natural products is a useful strategy for developing more potent anticancer agents by enhancing their bioavailability and avoiding drug resistance. METHODS:The in vivo activities of artemisinin-daumone hybrid 15 (ARTD) were estimated in cancer cell-inoculated mice and ovariectomized mice. The viability, migration, and invasion of cancer cells were measured via MTT, wound-healing, and transwell invasion assays. ARTD-regulated transcription factors were detected with an RT2 profiler PCR array kit and Western blotting. Osteoclastogenesis and osteoclast activity were detected with tartrate-resistant acid phosphatase staining, a pit formation assay, gelatin zymography, and a cathepsin K ELISA assay. RESULTS:ARTD blocked cancer-associated osteolysis more potently than artemisinin in mice with intratibially inoculated breast cancer or lung cancer cells. ARTD inhibited the viability, migration, and invasion of breast and lung cancer cells in the absence or presence of transforming growth factor-β1. ARTD treatment induced the expression of tumor suppressive activating transcription factor 3 and inhibited oncogenic E2F transcription factor 1 expression at the mRNA and protein levels. ARTD inhibited receptor activator of nuclear factor kappa-B ligand-induced osteoclast formation and bone resorbing activity by reducing the secreted levels of matrix metalloproteinase-9 and cathepsin K. Furthermore, ARTD prevented estrogen deficiency-induced bone loss in ovariectomized mice. CONCLUSION:ARTD may be a promising candidate for inhibiting cancer-induced bone destruction. The application of ARTD may be extended to patients with chemotherapy-induced ovarian failure or postmenopausal osteoporosis. 10.1159/000493449
    [Research progress on anti-cancer mechanisms of arsenic trioxide and artemisinin]. Yue Qing-xi,Yu Hong,He Ting,Yu Hai-qing Yao xue xue bao = Acta pharmaceutica Sinica The formation and metastasis of tumor cells are closely related to the gene regulation. It is critical to elucidate the molecular mechanism of a compound using in cancer therapy. In this article, we reviewed the anti-cancer molecular mechanism of arsenic trioxide and artemisinin. Its anti-cancer function mainly includes: regulation of cell cycle regulatory proteins to inhibit tumor cell proliferation, cell apoptosis signal transduction pathway to promote apoptosis in tumor cells, immortalization associated genes to reduce the life of tumor cells, angiogenesis/invasion/metastasis gene to block the spread of tumor cells, promoter methylation and protein ubiquitination gene to enhance anti-oncogene expression and ubiquitin- mediated protein degradation, micro RNA to inhibit proliferation or induce apoptosis in tumor cells, DNA synthesis and repair of DNA damage and repair gene to decrease the DNA synthesis of tumor cells, signal transduction pathways of cell proliferation/apoptosis and invasion/metastasis etc., the expression of hormone receptors and so on. We indicated the problems existing in current studies and also prospected the future of using the compound to fight cancer.
    Potential of bacterial culture media in biofabrication of metal nanoparticles and the therapeutic potential of the as-synthesized nanoparticles in conjunction with artemisinin against MDA-MB-231 breast cancer cells. Khan Badrealam Farheen,Hamidullah ,Dwivedi Sonam,Konwar Rituraj,Zubair Swaleha,Owais Mohammad Journal of cellular physiology In the recent past, various groups have proposed diverse biocompatible methods for the synthesis of metal nanoparticles (NPs). Besides culture biomass, culture supernatants (CS) are increasingly being explored for the synthesis of NPs; however, with the ever-increasing exploration of various CS in the biofabrication of NPs, it is equally important to explore the potential of various culture media (CMs) in the synthesis of metal NPs. Considering these aspects, in the present investigation, we explore the possible applicability of various CMs in the biofabrication of metal NPs. The synthesis of NPs was primarily followed by UV/VIS spectroscopy, and, thereafter, the NPs were characterized by various physiochemical techniques, including EM, EDX, FT_IR, X-ray diffraction, and DLS measurements, and finally, their anticancer potentialities were investigated against breast cancer. In addition, the NPs were examined in conjunction with artemisinin for therapeutic benefits against aggressive and highly metastatic MDA-MB-231 breast cancer cells. Cumulatively, the results of the present study collated the potentials of various bacterial CMs in the biofabrication of metal NPs and ascertained the efficacy of the as-synthesized silver nanoparticles, especially the combinatorial entity as intriguing breast cancer therapeutics. The data of the present study plausibly assist in advancing the therapeutic applicability of the combinatorial amalgam against aggressive and highly metastatic MDA-MB-231 breast cancer cells. 10.1002/jcp.27438
    Artemisinin-Derived Dimers: Potent Antimalarial and Anticancer Agents. Fröhlich Tony,Çapcı Karagöz Aysun,Reiter Christoph,Tsogoeva Svetlana B Journal of medicinal chemistry The development of new efficient therapeutics for the treatment of malaria and cancer is an important endeavor. Over the past 15 years, much attention has been paid to the synthesis of dimeric structures, which combine two units of artemisinin, as lead compounds of interest. A wide variety of atemisinin-derived dimers containing different linkers demonstrate improved properties compared to their parent compounds (e.g., circumventing multidrug resistance), making the dimerization concept highly compelling for development of efficient antimalarial and anticancer drugs. The present Perspective highlights recent developments on different types of artemisinin-derived dimers and their structural and functional features. Particular emphasis is put on the respective in vitro and in vivo studies, exploring the role of the length and nature of linkers on the activities of the dimers, and considering the future prospects of the dimerization concept for drug discovery. 10.1021/acs.jmedchem.5b01380
    Artemisinin inhibits monocyte adhesion to HUVECs through the NF-κB and MAPK pathways in vitro. Wang Yue,Cao Jiatian,Fan Yuqi,Xie Yushui,Xu Zuojun,Yin Zhaofang,Gao Lin,Wang Changqian International journal of molecular medicine The adhesion of monocytes to human umbilical vein endothelial cells (HUVECs) plays a crucial role in the initiation of atherosclerosis. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are two important molecules involved in the adhesion of monocytes to HUVECs. Previous studies have suggested that artemisinin, apart from an anti-malarial agent, also has other effects. In the present study, we found that artemisinin significantly decreased the adhesion of monocytes to tumor necrosis factor-α (TNF-α)-stimulated HUVECs in a dose-dependent manner and suppressed the mRNA and protein level of ICAM-1 and VCAM-1 in the TNF-α-stimulated HUVECs. In addition, the nuclear factor-κB (NF-κB) inhibitor, Bay 11-7082, and mitogen-activated protein kinase (MAPK) inhibitors (SB203580 and U0126) respectively reduced the adhesion of monocytes to TNF-α-stimulated HUVECs, and suppressed ICAM-1 and VCAM-1 expression in TNF-α stimulated HUVECs. Moreover, artemisinin impeded the activation of the NF-κB and MAPK signaling pathways. Furthermore, Bay 11-7082 significantly decreased the phosphorylation of levels extracellular signal-regulated protein kinase (ERK)1/2, p38 and c-Jun N-terminal kinase (JNK). Taken together, the findings of our study indicated that artemisinin blocked monocyte adhesion to TNF-α-stimulated to HUVECs by downregulating ICAM-1 and VCAM-1 expression in the TNF-α-stimulated HUVECs. Artemisinin may thus have potential for use in the protection against the early development of atherosclerotic lesions. 10.3892/ijmm.2016.2579
    Evaluation of artemisinins for the treatment of acute myeloid leukemia. Drenberg Christina D,Buaboonnam Jassada,Orwick Shelley J,Hu Shuiying,Li Lie,Fan Yiping,Shelat Anang A,Guy R Kiplin,Rubnitz Jeffrey,Baker Sharyn D Cancer chemotherapy and pharmacology PURPOSE:Investigate antileukemic activity of artemisinins, artesunate (ART), and dihydroartemisinin (DHA), in combination with cytarabine, a key component of acute myeloid leukemia (AML) chemotherapy using in vitro and in vivo models. METHODS:Using ten human AML cell lines, we conducted a high-throughput screen to identify antimalarial agents with antileukemic activity. We evaluated effects of ART and DHA on cell viability, cytotoxicity, apoptosis, lysosomal integrity, and combination effects with cytarabine in cell lines and primary patient blasts. In vivo pharmacokinetic studies and efficacy of single-agent ART or combination with cytarabine were evaluated in three xenograft models. RESULTS:ART and DHA had the most potent activity in a panel of AML cell lines, with selectivity toward samples harboring MLL rearrangements and FLT3-ITD mutations. Combination of ART or DHA was synergistic with cytarabine. Single-dose ART (120 mg/kg) produced human equivalent exposures, but multiple dose daily administration required for in vivo efficacy was not tolerated. Combination treatment produced initial regression, but did not prolong survival in vivo. CONCLUSIONS:The pharmacology of artemisinins is problematic and should be considered in designing AML treatment strategies with currently available agents. Artemisinins with improved pharmacokinetic properties may offer therapeutic benefit in combination with conventional therapeutic strategies in AML. 10.1007/s00280-016-3038-2
    Artemisinin inhibits gastric cancer cell proliferation through upregulation of p53. Zhang Hong-Tao,Wang Yun-Long,Zhang Jie,Zhang Qin-Xian Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine Recent population studies suggest that the use of artemisinin is associated with reduced incidence and improved prognosis of certain cancers. In the current study, we assessed the effect of artemisinin on gastric cancer cells (AGS and MKN74 cells). We found that artemisinin inhibited growth and modulated expression of cell-cycle regulators in these cells. Treatment with artemisinin was also associated with induction of p27 kip1 and p21 kip1, two negative cell-cycle regulators. Furthermore, we revealed that artemisinin treatment led to an increased expression of p53. Taken together, these results provide evidence for a mechanism that may contribute to the antineoplastic effects of artemisinin suggested by recent population studies and justify further work to explore potential roles for it in gastric cancer prevention and treatment. 10.1007/s13277-013-1193-1
    Artemisinin reduces cell proliferation and induces apoptosis in neuroblastoma. Zhu Shunqin,Liu Wanhong,Ke Xiaoxue,Li Jifu,Hu Renjian,Cui Hongjuan,Song Guanbin Oncology reports Artemisinin, a natural product from the Chinese medicinal plant, Artemisia annua L., is commonly used in the treatment of malaria, and has recently been reported to have potent anticancer activity in various types of human tumors. Yet, the effect of artemisinin on neuroblastoma is still unclear. In the present study, we aimed to investigate the effects of artemisinin on neuroblastoma cells. We observed that artemisinin significantly inhibited cell growth and proliferation, and caused cell cycle arrest in the G1 phase in neuroblastoma cell lines. Annexin V-FITC/PI staining assay revealed that artemisinin markedly induced apoptosis. Soft agar assays revealed that artemisinin suppressed the ability of clonogenic formation of neuroblastoma cells and a xenograft study in NOD/SCID mice showed that artemisinin inhibited tumor growth and development in vivo. Therefore, our results suggest that the Chinese medicine artemisinin could serve as a novel potential therapeutic agent in the treatment of neuroblastoma. 10.3892/or.2014.3323
    Novel spirobicyclic artemisinin analogues (artemalogues): Synthesis and antitumor activities. Liu Gang,Song Shanshan,Shu Shiqi,Miao Zehong,Zhang Ao,Ding Chunyong European journal of medicinal chemistry The sesquiterpene lactone framework of artemisinin was used as a drug repositioning prototype for the development of novel antitumor drugs. Several series of novel artemisinin analogues (artemalogues) were designed and synthesized through 1,3-dipolar cycloaddition of artemisitene with nitrile oxides or nitrones. The isoxazolidine-containing spirobicyclic artemalogue 11b turns out to be the most potent with low micromolar IC₅₀ values against all three tumor cells, which were at least 4- to 14-fold more potent than the parent artemisinin. 10.1016/j.ejmech.2015.08.035
    Preparation, characterization and in vitro efficacy of magnetic nanoliposomes containing the artemisinin and transferrin. Gharib Amir,Faezizadeh Zohreh,Mesbah-Namin Seyed Ali Reza,Saravani Ramin Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences BACKGROUND:Artemisinin is the major sesquiterpene lactones in sweet wormwood (Artemisia annua L.), and its combination with transferrin exhibits versatile anti-cancer activities. Their non-selective targeting for cancer cells, however, limits their application. The aim of this study was to prepare the artemisinin and transferrin-loaded magnetic nanoliposomes in thermosensitive and non-thermosensitive forms and evaluate their antiproliferative activity against MCF-7 and MDA-MB-231 cells for better tumor-targeted therapy. METHODS:Artemisinin and transferrin-loaded magnetic nanoliposomes was prepared by extrusion method using various concentrations of lipids. These formulations were characterized for particle size, zeta potential, polydispersity index and shape morphology. The artemisinin and transferrin-loading efficiencies were determined using HPLC. The content of magnetic iron oxide in the nanoliposomes was analysed by spectrophotometry. The in vitro release of artemisinin, transferrin and magnetic iron oxide from vesicles was assessed by keeping of the nanoliposomes at 37°C for 12 h. The in vitro cytotoxicity of prepared nanoliposomes was investigated against MCF-7 and MDA-MB-231 cells using MTT assay. RESULTS:The entrapment efficiencies of artemisinin, transferrin and magnetic iron oxide in the non-thermosensitive nanoliposomes were 89.11% ± 0.23, 85.09% ± 0.31 and 78.10% ± 0.24, respectively. Moreover, the thermosensitive formulation showed a suitable condition for thermal drug release at 42°C and exhibited high antiproliferative activity against MCF-7 and MDA-MB-231 cells in the presence of a magnetic field. CONCLUSIONS:Our results showed that the thermosensitive artemisinin and transferrin-loaded magnetic nanoliposomes would be an effective choice for tumor-targeted therapy, due to its suitable stability and high effectiveness. 10.1186/2008-2231-22-44
    Design and Development of Nanostructured Co Delivery of Artemisinin and Chrysin for Targeting hTERT Gene Expression in Breast Cancer Cell Line: Possible Clinical Application in Cancer Treatment. Asian Pacific journal of cancer prevention : APJCP BACKGROUND:Breast cancer is one of the most significant causes of female cancer death worldwide. To explore the possibility of a novel chemo-preventive strategy for improving breast cancer treatment, the anticancer effects of two natural compounds, Artemisinin (Art) and Chrysin (Chr), against T47D breast cancer cells were investigated. METHODS:For this purpose, Art and Chr were co-encapsulated in PEGylated PLGA nanoparticles (NPs) and the synthesized NPs were characterized by FE-SEM, FTIR, and DLS and then, MTT assay was used to assess and compare the cytotoxicity of various concentrations of the chemotheruptic molecules in pure and nanoformulated forms as well as in alone and combination state after 48 h exposure time. Drug release study was performed using the dialysis method. Also, the mRNA levels of hTERT genes expression were studied by quantitative real-time PCR. RESULTS:The results showed that pure and formulations drugs exhibited dose-dependent cytotoxicity against T47D cells and especially, Art/Chr-PLGA/PEG NPs had a more synergistic anti-proliferative effect and significantly arrested the growth of cancer cells than the other groups. Moreover, Real-time PCR results revealed that Art, Chr and combination of Art-Chr in pure and encapsulated forms inhibited hTERT gene expression. CONCLUSIONS:It was found that Art/Chr-PLGA/PEG NPs relative to pure combination could further decline hTERT expression in all concentrations. Our study demonstrated that Art/Chr-PLGA/PEG NPs based combinational therapy holds promising potential for the treatment of breast cancer. 10.31557/APJCP.2022.23.3.919
    Artemisinin inhibits the proliferation, migration, and inflammatory reaction induced by tumor necrosis factor-α in vascular smooth muscle cells through nuclear factor kappa B pathway. Cao Qian,Jiang Yan,Shi Jin,Xu Changlu,Liu Xiaoxia,Yang Tiangui,Fu Peng,Niu Tiesheng The Journal of surgical research BACKGROUND:Atherosclerosis is an inflammatory disease with the most common pathologic process leading to cardiovascular diseases. The aim of this study was to evaluate the effect of artemisinin (ART) on the proliferation, migration, and inflammation induced by tumor necrosis factor-α (TNF-α) of rat vascular smooth muscle cells (VSMCs). MATERIALS AND METHODS:Primary rat VSMCs were pretreated with ART and then co-incubated with TNF-α. Cell proliferation was evaluated by MTT assay. Cell migration was assessed by transwell assay. Reactive oxygen species (ROS) production was measured by flow cytometry after staining with dichloro-dihydro-fluorescein diacetate. Inflammation factors of nitric oxide and prostaglandin E2 (PGE2) were measured by responding assay kits. Expression levels of nuclear factor kappa B (NF-κB) subunit NF-κB p65 and the regulator inhibitor of nuclear factor kappa-B kinase-alpha (IκBα) were tested by Western blot, meanwhile, the activation of NF-κB was observed by immunofluorescence assay. RESULTS:The proliferation, migration, and inflammation of VSMCs induced by TNF-α were significantly inhibited by ART treatment in a dose-dependent manner. Treatment with 100 μM ART for 2 h significantly reduced the expression of proliferating cell nuclear antigen and migration-related proteins matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). On the other hand, the same treatment decreased the inflammation factors production of nitric oxide and PGE2. Fluorescence-activated cell sorting analysis revealed that ART suppressed the ROS production induced by TNF-α. Western blot analysis showed that both inflammation mediators inducible nitric oxide synthase and cyclooxygenase and the NF-κB pathway subunit NF-κB p65 were downregulated by ART. CONCLUSIONS:The results suggest that ART can effectively inhibit the proliferation, migration, and inflammation of VSMCs induced by TNF-α through ROS-mediated NF-κB signal pathway. 10.1016/j.jss.2014.12.013
    A mitochondria-targeting artemisinin derivative with sharply increased antitumor but depressed anti-yeast and anti-malaria activities. Sun Chen,Cao Yu,Zhu Pan,Zhou Bing Scientific reports The potent anti-malarial drug artemisinins are additionally anti-tumorigenic and inhibitory to yeast growth. The action mechanism of artemisinins, however, is not well understood. Heme and mitochondrial membrane are both suggested to be involved in the action of artemisinins. Because heme is also synthesized in the mitochondrion, mitochondria appear to be a critical organelle for artemisinins' activities. In this study, we synthesized a mitochondria-targeting artemisinin derivative by conjugating triphenylphosphonium (TPP) to artelinic acid (ARTa). ARTa-TPP displays far more potent anti-tumorigenic activity than its parent compound. In contrast, ARTa-TPP is much less active against yeast respiration growth and malarial parasites. Notably, ARTa-TPP is also associated with increased toxicity to other kinds of control mammalian cells. These results suggest divergent action modes for artemisinins against cancer cells and malaria or yeast cells. We conclude that mitochondrial targeting could substantially elevate the anticancer potency of artemisinins, but the accompanied increased toxicity to normal cells raises an alert. The mechanism regarding the opposing effects of TPP conjugation to ARTa on its anticancer and anti-malarial/anti-yeast potencies is discussed based on our current understandings of artemisinins' action. 10.1038/srep45665
    Artemisinin derivatives inhibit epithelial ovarian cancer cells via autophagy-mediated cell cycle arrest. Li Boning,Bu Shixia,Sun Junyan,Guo Ying,Lai Dongmei Acta biochimica et biophysica Sinica Epithelial ovarian cancer (EOC) is the most fatal gynecologic malignancy due to its late diagnosis and lack of curative therapy. The antimalaria compound artemisinin and its derivatives, such as artesunate (ART) and dihydroartemisinin (DHA), have proven to be potent anticancer drugs and act through various anticancer mechanisms. To identify novel targets of artemisinin derivatives in EOC cells, we investigated the effects of ART and DHA on SKOV3 and primary EOC cell growth via CCK-8 assay. Both ART and DHA inhibited EOC cell growth. A cell cycle distribution analysis showed that ART and DHA caused G2/M cell cycle arrest. Moreover, ART and DHA induced autophagy in EOC cells, whereas autophagy inhibitors reversed the cell growth inhibition and cell cycle arrest induced by ART and DHA. Western blot analysis showed that ART and DHA also suppressed the cell cycle-related NF-κB-signaling pathway in EOC cells. These data suggest that artemisinin derivatives induce autophagy, block the cell cycle, and inhibit cell growth in EOC cells. Our research provides new targets for artemisinin derivatives for EOC treatment. 10.1093/abbs/gmy125
    Multifunctional mesoporous nanoparticles as pH-responsive Fe(2+) reservoirs and artemisinin vehicles for synergistic inhibition of tumor growth. Chen Jian,Guo Zhen,Wang Hai-Bao,Zhou Jia-Jia,Zhang Wei-Jie,Chen Qian-Wang Biomaterials Artemisinin (ART) is an iron-dependent anti-cancer drug. However, simultaneous delivery of hydrophobic ART and Fe(2+) ions into cancer cells remains a major challenge. Herein, we reported Fe3O4@C/Ag@mSiO2 (FCA@mSiO2) multifunctional nanocarriers which can load ART as high as 484 mg/g. Moreover, FCA@mSiO2 nanoparticles demonstrated pH-responsive Fe(2+) release, the concentration of Fe(2+) ions can reach 2.765 nmol/L in HeLa cells cultured with FCA@mSiO2 nanoparticles. The antitumor efficacy of ART-loaded FCA@mSiO2 nanoparticles measured by MTT assay was significantly enhanced compared with free ART. It was suggested that the ART-loaded FCA@mSiO2 nanoparticles are internalized by HeLa cells and located at the acidic compartments of endosomes and lysosomes, releasing Fe(2+) ions to non-enzymatically convert ART to toxic products for killing cancer cells. This result provides a way for using promising natural drugs in anti-cancer therapeutics. 10.1016/j.biomaterials.2014.04.028
    Synthesis and cytotoxic activity of new artemisinin hybrid molecules against human leukemia cells. Letis Antonios S,Seo Ean-Jeong,Nikolaropoulos Sotiris S,Efferth Thomas,Giannis Athanassios,Fousteris Manolis A Bioorganic & medicinal chemistry A series of new artemisinin-derived hybrids which incorporate cholic acid moieties have been synthesized and evaluated for their antileukemic activity against sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 cells. The new hybrids 20-28 showed IC values in the range of 0.019µM-0.192µM against CCRF-CEM cells and between 0.345µM and 7.159µM against CEM/ADR5000 cells. Amide hybrid 25 proved the most active compound against both CCRF-CEM and CEM/ADR5000 cells with IC value of 0.019±0.001µM and 0.345±0.031µM, respectively. A relatively low cross resistance to hybrids 20-28 in the range of 5.7-fold to 46.1-fold was measured. CEM/ADR5000 cells showed higher resistance than CCRF-CEM to all the tested compounds. Interestingly, the lowest cross resistance to 23 was observed (5.7-fold), whereas hybrid 25 showed 18.2-fold cross-resistant to CEM/ADR5000 cells. Hybrid 25 which proved even more potent than clinically used doxorubicin against CEM/ADR5000 cells may serve as a promising antileukemic agent against both sensitive and multidrug-resistant cells. 10.1016/j.bmc.2017.04.021
    Effects of dihydroartemisinin, a metabolite of artemisinin, on colon cancer chemoprevention and adaptive immune regulation. Wang Chong-Zhi,Wan Chunping,Luo Yun,Zhang Chun-Feng,Zhang Qi-Hui,Chen Lina,Liu Zhi,Wang Daniel H,Lager Mallory,Li Cang-Hai,Jiang Ting-Liang,Hou Lifei,Yuan Chun-Su Molecular biology reports BACKGROUND:Artemisinin (ART) is an anti-malaria natural compound with a moderate anticancer action. As a metabolite of ART, dihydroartemisinin (DHA) may have stronger anti-colorectal cancer (CRC) bioactivities. However, the effects of DHA and ART on CRC chemoprevention, including adaptive immune regulation, have not been systematically evaluated and compared. METHODS:Coupled with a newly-established HPLC analytical method, enteric microbiome biotransformation was conducted to identify if the DHA is a gut microbial metabolite of ART. The anti-CRC potential of these compounds was compared using two different human CRC cell lines for cell cycle arrest, apoptotic induction, and anti-inflammation activities. Naive CD4 T cells were also obtained for testing the compounds on the differentiation of Treg, Th1 and Th17. RESULTS:Using compound extraction and analytical methods, we observed for the first time that ART completely converted into its metabolites by gut microbiome within 24 h, but no DHA was detected. Although ART did not obviously influence cancer cell growth in the concentration tested, DHA very significantly inhibited the cancer cell growth at relatively low concentrations. DHA included G2/M cell cycle arrest via upregulation of cyclin A and apoptosis. Both ART and DHA downregulated the pro-inflammatory cytokine expression. The DHA significantly promoted Treg cell proliferation, while both ART and DHA inhibited Th1 and Th17 cell differentiation. CONCLUSIONS:As a metabolite of ART, DHA possessed stronger anti-CRC activities. The DHA significantly inhibited cell growth via cell cycle arrest, apoptosis induction and anti-inflammation actions. The adaptive immune regulation is a related mechanism of actions for the observed effects. 10.1007/s11033-021-07079-1
    Comparative cytotoxicity of artemisinin and cisplatin and their interactions with chlorogenic acids in MCF7 breast cancer cells. Suberu John O,Romero-Canelón Isolda,Sullivan Neil,Lapkin Alexei A,Barker Guy C ChemMedChem In parts of Africa and Asia, self-medication with a hot water infusion of Artemisia annua (Artemisia tea) is a common practice for a number of ailments including malaria and cancer. In our earlier work, such an extract showed better potency than artemisinin alone against both chloroquine-sensitive and -resistant parasites. In this study, in vitro tests of the infusion in MCF7 cells showed high IC50 values (>200 μM). The combination of artemisinin and 3-caffeoylquinic acid (3CA), two major components in the extract, was strongly antagonistic and gave a near total loss of cytotoxicity for artemisinin. We observed that the interaction of 3CAs with another cytotoxic compound, cisplatin, showed potentiation of activity by 2.5-fold. The chelation of cellular iron by 3CA is hypothesized as a possible explanation for the loss of artemisinin activity. 10.1002/cmdc.201402285
    Artemisinin Represses Telomerase Subunits and Induces Apoptosis in HPV-39 Infected Human Cervical Cancer Cells. Mondal Anushree,Chatterji Urmi Journal of cellular biochemistry Artemisinin, a plant-derived antimalarial drug with relatively low toxicity on normal cells in humans, has selective anticancer activities in various types of cancers, both in vitro and in vivo. In the present study, we have investigated the anticancer effects of artemisinin in human cervical cancer cells, with special emphasis on its role in inducing apoptosis and repressing cell proliferation by inhibiting the telomerase subunits, ERα which is essential for maintenance of the cervix, and downstream components like VEGF, which is known to activate angiogenesis. Effects of artemisinin on apoptosis of ME-180 cells were measured by flow cytometry, DAPI, and annexin V staining. Expression of genes and proteins related to cell proliferation and apoptosis was quantified both at the transcriptional and translational levels by semi-quantitative RT-PCR and western blot analysis, respectively. Our findings demonstrated that artemisinin significantly downregulated the expression of ERα and its downstream component, VEGF. Antiproliferative activity was also supported by decreased telomerase activity and reduced expression of hTR and hTERT subunits. Additionally, artemisinin reduced the expression of the HPV-39 viral E6 and E7 components. Artemisinin-induced apoptosis was confirmed by FACS, nuclear chromatin condensation, annexin V staining. Increased expression of p53 with concomitant decrease in expression of the p53 inhibitor Mdm2 further supported that artemisinin-induced apoptosis was p53-dependent. The results clearly indicate that artemisinin induces antiproliferative and proapoptotic effects in HPV-39-infected ME-180 cells, and warrants further trial as an effective anticancer drug. 10.1002/jcb.25152
    Artemisinin modulating effect on human breast cancer cell lines with different sensitivity to cytostatics. Chekhun V F,Lukianova N Yu,Borikun T V,Zadvorny T V,Mokhir A Experimental oncology AIM:To explore effects of Artemisinin on a series of breast cancer cells with different sensitivity to typical cytotoxic drugs (doxorubicin - Dox; cisplatin - DDP) and to investigate possible artemisinin-induced modification of the mechanisms of drug resistance. MATERIALS AND METHODS:The study was performed on wild-type breast cancer MCF-7 cell line (MCF-7/S) and its two sublines MCF-7/Dox and MCF-7/DDP resistant to Dox and DDP, respectively. The cells were treated with artemisinin and iron-containing magnetic fluid. The latter was added to modulate iron levels in the cells and explore its role in artemisinin-induced effects. The MTT assay was used to monitor cell viability, whereas changes of expression of selected proteins participating in regulation of cellular iron homeostasis were estimated using immunocytochemical methods. Finally, relative expression levels of miRNA-200b, -320a, and -34a were examined by using qRT-PCR. RESULTS:Artemisinin affects mechanisms of the resistance of breast cancer cells towards both Dox and DDP at sub-toxic doses. The former drug induces changes of expression of iron-regulating proteins via different mechanisms, including epigenetic regulation. Particularly, the disturbances in ferritin heavy chain 1, lactoferrin, hepcidin (decrease) and ferroportin (increase) expression (р ≤ 0.05) were established. The most enhanced increase of miRNA expression under artemisinin influence were found for miRNA-200b in MCF-7/DDP cells (7.1 ± 0.98 fold change), miRNA-320a in MCF-7/Dox cells (2.9 ± 0.45 fold change) and miRNA-34a (1.7 ± 0.15 fold change) in MCF-7/S cells. It was observed that the sensitivity to artemisinin can be influenced by changing iron levels in cells. CONCLUSIONS:Artemisinin can modify iron metabolism of breast cancer cells by its cytotoxic effect, but also by inducing changes in expression of iron-regulating proteins and microRNAs (miRNAs), involved in their regulation. This modification affects the mechanisms that are implicated in drug-resistance, that makes artemisinin a perspective modulator of cell sensitivity towards chemotherapeutic agents in cancer treatment.
    Artemisinin inhibits gallbladder cancer cell lines through triggering cell cycle arrest and apoptosis. Jia Jianguang,Qin Yiyu,Zhang Ligong,Guo Chenxu,Wang Yaguo,Yue Xicheng,Qian Jun Molecular medicine reports Primary gallbladder cancer (GBC) is the most common malignancy of the digestive system. Due to its resistance to standard chemotherapy, no effective treatments are available at present. Artemisinin, a plant-derived anti‑malarial drug, has recently been shown to have anti-proliferative effects on a range of human cancer cell types. However, the efficacy of artemisinin against gallbladder cancer has not been reported. The present study investigated the effects of artemisinin on the proliferation, cell cycle and apoptosis of gallbladder cancer cell lines. A cell viability assay and an in vivo xenograft study demonstrated that artemisinin significantly inhibited the growth of gallbladder cancer. Western blot analysis indicated that artemisinin induced the expression of p16, while down‑regulating phosphorylated extracellular signal‑regulated kinase (ERK)1/2, CDK4 and cyclin D1 expression, leading to inhibition of the ERK1/2 pathway. Furthermore, flow cytometry and western blot analysis showed that artemisinin caused G1-phase arrest of the cell cycle, promoted the generation of reactive oxygen species (ROS), led to a collapse of the mitochondrial membrane potential and to triggered cytochrome c release from the mitochondria into the cytoplasm, which finally activated caspase‑3‑mediated apoptosis. In conclusion, the present study demonstrated that artemisinin inhibits the proliferation of gallbladder cancer cells in vitro as well as in vivo and induces apoptosis via induction of ROS and cell cycle arrest. These results suggested that artemisinin may be suitable for the treatment of gallbladder cancer. 10.3892/mmr.2016.5073
    pH-dependent reversibly activatable cell-penetrating peptides improve the antitumor effect of artemisinin-loaded liposomes. Yu Yinglan,Zu Chang,He Dongsheng,Li Yanan,Chen Qinying,Chen Qian,Wang Huimin,Wang Ruijuan,Chaurasiya Birendra,Zaro Jennica L,Wang Yiran,Tu Jiasheng,Sun Chunmeng Journal of colloid and interface science Artemisinin (ART) is well known as an antimalarial drug, and it can also be used to treat inflammation as well as cancer. Although many researchers have reported the antitumor activity of ART, most of these studies were investigated in vitro. In addition, ART is sparingly soluble in water, limiting its clinical relevance in drug development. Based on the data from our preliminary study, ART is not cytotoxic at low micromolar concentrations. Thus, we hypothesized that smart nanocarriers are beneficial for not only increasing the solubility of ART but also elevating the concentration of the drug at the target, thereby inducing the ideal antitumor effect. In this article, a reversibly activatable cell-penetrating peptide ((HE)-G-R or HE-R) was introduced to modify artemisinin (ART)-loaded liposomes (ART-Lip-HE-R) against tumors, and in vitro and in vivo performance were investigated. ART-Lip-HE-R exhibited sustained release under different pH conditions. The internalization and cytotoxicity of liposomes were enhanced at low pH, i.e., 6.5, after modification with HE-R versus nonmodified liposomes. Moreover, a longer retention time in tumors could be observed in the ART-Lip-HE-R group, followed by higher efficiency of tumor suppression. In conclusion, Lip-HE-R might be a promising delivery system for ART in cancer therapy. 10.1016/j.jcis.2020.10.103
    Enhanced Efficacy of Artemisinin Loaded in Transferrin-Conjugated Liposomes versus Stealth Liposomes against HCT-8 Colon Cancer Cells. Leto Isabella,Coronnello Marcella,Righeschi Chiara,Bergonzi Maria Camilla,Mini Enrico,Bilia Anna Rita ChemMedChem Artemisinin (ART) is a unique sesquiterpene lactone isolated from Artemisia annua that is well known for antimalarial properties and was recently reported as a promising anticancer drug. The aim of our work was to develop a novel nanocarrier for enhanced ART delivery and activation in cancer tissues, because transferrin receptors are largely expressed in cancer cells and the iron content is higher than in normal cells. ART was loaded in transferrin-conjugated liposomes (ART-L-Tf), and the performance was compared with ART loaded in stealth liposomes (ART-L). All of the liposomes were fully characterized in terms of size, drug-entrapment efficiency, transferrin coupling moieties, and stability. Both cell uptake and cytotoxicity studies of the developed nanocarriers were tested in the HCT-8 cell line, selected among several cell lines because of transferrin receptor overexpression. The results confirmed the enhanced delivery of ART-L-Tf in comparison with ART-L in the targeting of the HCT-8 cell line and an improved cytotoxicity as a result of the presence of iron ions, which resulted in concomitant synergism derived from the increased expression of transferrin receptors on the surface of the tumor cells. 10.1002/cmdc.201500586
    Prevention of carcinogenesis and metastasis by Artemisinin-type drugs. Abba Mohammed L,Patil Nitin,Leupold Jörg Hendrik,Saeed Mohamed E M,Efferth Thomas,Allgayer Heike Cancer letters Artemisia annua (sweet wormwood, qinhao) is an ancient Chinese herbal remedy for pyrexia. Nowadays, artemisinin (qinghaosu) and its derivatives belong to the standard therapies against malaria worldwide, and its discovery has led to the Nobel Prize in Physiology and Medicine to Youyou Tu in 2015. While most attention has been paid to the treatment of malaria, there is increasing evidence that Artemisinin-type drugs bear a considerable potential to treat and prevent cancer. Rather than reporting on therapy of cancer, this review gives a comprehensive and timely overview on the chemopreventive effects of artemisinin and its derivatives against carcinogenesis and metastasis formation, following the multistage model of carcinogenesis (initiation, promotion, progression). The favorable toxicity profile known from malaria studies indicates that artemisinin-type drugs may be safely applied to prevent carcinogenesis and cancer metastasis in human beings. 10.1016/j.canlet.2018.05.008
    Preclinical Efficacy and Safety Assessment of Artemisinin-Chemotherapeutic Agent Conjugates for Ovarian Cancer. Li Xiaoguang,Zhou Yu,Liu Yanling,Zhang Xu,Chen Tao,Chen Kerong,Ba Qian,Li Jingquan,Liu Hong,Wang Hui EBioMedicine Artemisinin (ARS) and its derivatives, which are clinically used antimalarial agents, have shown antitumor activities. Their therapeutic potencies, however, are limited by their low solubility and poor bioavailability. Here, through a pharmacophore hybridization strategy, we synthesized ARS-drug conjugates, in which the marketed chemotherapeutic agents chlorambucil, melphalan, flutamide, aminoglutethimide, and doxifluridine, were separately bonded to Dihydroartemisinin (DHA) through various linkages. Of these, the artemisinin-melphalan conjugate, ARS4, exhibited most toxicity to human ovarian cancer cells but had low cytotoxicity to normal cells. ARS4 inhibited the growth and proliferation of ovarian cancer cells and resulted in S-phase arrest, apoptosis, and inhibition of migration; these effects were stronger than those of its parent drugs, DHA and melphalan. Furthermore, ARS4 modulated the expression of proteins involved in cell cycle progression, apoptosis, and the epithelial-mesenchymal transition (EMT). Moreover, in mice, ARS4 inhibited growth and intraperitoneal dissemination and metastasis of ovarian cancer cells without observable toxic effects. Our results provide a basis for development of the compound as a chemotherapeutic agent. RESEARCH IN CONTEXT:Artemisinin compounds have recently received attention as anticancer agents because of their clinical safety profiles and broad efficacy. However, their therapeutic potencies are limited by low solubility and poor bioavailability. Here, we report that ARS4, an artemisinin-melphalan conjugate, possesses marked in-vitro and in-vivo antitumor activity against ovarian cancer, the effects of which are stronger than those for its parent drugs, Dihydroartemisinin and melphalan. In mice, ARS4 inhibits localized growth of ovarian cancer cells and intraperitoneal dissemination and metastasis without appreciable host toxicity. Thus, for patients with ovarian cancer, ARS4 is a promising chemotherapeutic agent. 10.1016/j.ebiom.2016.11.026
    Inhibition of metalloproteinase-9 secretion and gene expression by artemisinin derivatives. Magenta Daniele,Sangiovanni Enrico,Basilico Nicoletta,Haynes Richard K,Parapini Silvia,Colombo Elisa,Bosisio Enrica,Taramelli Donatella,Dell'Agli Mario Acta tropica Malaria remains one of the world's most common infectious diseases, being responsible for more deaths than any other communicable disease except tuberculosis. There is strong evidence that tumour necrosis factor α and interleukin-1β are important contributors to the systemic disease caused by the infection with Plasmodium falciparum. Circulating levels of TNFα are increased after infection, as a consequence of stimulation of monocyte-macrophages by infected red blood cells or parasite products, as shown in vitro for the malaria pigment haemozoin. TNFα in turn enhances the synthesis of metalloproteinase-9 in monocytes and macrophages. Metalloproteinase-9 acts on the extracellular matrix but also on non-traditional substrates, including precursors of inflammatory cytokines, which are proteolytically activated and contribute to the amplification of the inflammatory response. The aim of the present work was to establish whether artemisinin and its derivatives artemisone, artesunate and dihydroartemisinin possess immuno-modulatory properties. In particular, it is necessary to evaluate their effects on mRNA levels and secretion of MMP-9 by the human monocytic cell line (THP-1 cells) stimulated by hemozoin or TNFα. 5μM of each derivative, although not artemisinin itself, induced significantly inhibited TNFα production. Artesunate, artemisone and DHA antagonized haemozoin-induced MMP-9 secretion by 25%, 24% and 50%, respectively. mRNA levels were also depressed by 14%, 20% and 27%, respectively, thus reflecting in part the effect observed on protein production. The derivatives significantly inhibited both TNFα-induced MMP-9 secretion and mRNA levels to a greater extent than haemozoin itself. Both haemozoin and TNFα increased NF-κB driven transcription by 11 and 7.7 fold, respectively. Artesunate, artemisone and DHA inhibited haemozoin-induced NF-κB driven transcription by 28%, 34%, and 49%, respectively. Similarly the derivatives, but not artemisinin, prevented TNFα-induced NF-κB driven transcription by 47-51%. The study indicates that artemisinins may attenuate the inflammatory potential of monocytes in vivo. Thus, in addition to direct anti-parasitic activities, the beneficial clinical effects of artemisinins for the treatment of malaria include the apparent ability to attenuate the inflammatory response, thus limiting the risk of progression to the more severe form of the disease, including the onset of cerebral malaria. 10.1016/j.actatropica.2014.08.008
    Activity of Artemisia annua and artemisinin derivatives, in prostate carcinoma. Michaelsen Friedrich-Wilhelm,Saeed Mohamed E M,Schwarzkopf Jörg,Efferth Thomas Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:Artemisia annua L, artemisinin and artesunate reveal profound activity not only against malaria, but also against cancer in vivo and clinical trials. Longitudinal observations on the efficacy of A. annua in patients are, however missing as of yet. METHODS:Clinical diagnosis was performed by imaging techniques (MRT, scintigraphy, SPECT/CT) and blood examinations of standard parameters from clinical chemistry. Immunohistochemistry of formalin-fixed, paraffin-embedded tumor material was performed to determine the expression of several biomarkers (cycloxygenase-2 (COX2), epidermal growth factor receptor (EGFR), glutathione S-transferase P1 (GSTP1), Ki-67, MYC, oxidized low density lipoprotein (lectin-like) receptor 1 (LOX1), p53, P-glycoprotein, transferrin receptor (TFR, CD71), vascular endothelial growth factor (VEGF), von Willebrand factor (CD31)). The immunohistochemical expression has been compared with the microarray-based mRNA expression of these markers in two prostate carcinoma cell lines (PC-3, DU-145). RESULTS:A patient with prostate carcinoma (pT3bN1M1, Gleason score 8 (4+4)) presented with a prostate specific antigen (PSA) level >800 µg/l. After short-term treatment with bacalitumide (50 mg/d for 14 days) and long-term oral treatment with A. annua capsules (continuously 5 × 50 mg/d), the PSA level dropped down to 0.98 µg/l. MRT, scintigraphy and SPECT/CT verified tumor remission. Seven months later, PSA and ostase levels increased, indicating tumor recurrence and skeletal metastases. Substituting A. annua capsules by artesunate injections (2 × 150 mg twice weekly i.v.) did not prohibit tumor recurrence. PSA and ostase levels rose to 1245 µg/l and 434 U/l, respectively, and MRT revealed progressive skeletal metastases, indicating that the tumor acquired resistance. The high expression of MYC, TFR, and VEGFC in the patient biopsy corresponded with high expression of these markers in the artemisinin-sensitive PC-3 cells compared to artemisinin-resistant DU-145 cells. CONCLUSION:Long-term treatment with A. annua capsules combined with short-term bicalitumide treatment resulted in considerable regression of advanced metastasized prostate carcinoma. Controlled clinical trials are required to evaluate the clinical benefit of A. annua in prostate cancer. 10.1016/j.phymed.2015.11.001
    Synthesis, in vitro antimalarial activities and cytotoxicities of amino-artemisinin-ferrocene derivatives. de Lange Christo,Coertzen Dina,Smit Frans J,Wentzel Johannes F,Wong Ho Ning,Birkholtz Lyn-Marie,Haynes Richard K,N'Da David D Bioorganic & medicinal chemistry letters Novel derivatives bearing a ferrocene attached via a piperazine linker to C-10 of the artemisinin nucleus were prepared from dihydroartemisinin and screened against chloroquine (CQ) sensitive NF54 and CQ resistant K1 and W2 strains of Plasmodium falciparum (Pf) parasites. The overall aim is to imprint oxidant (from the artemisinin) and redox (from the ferrocene) activities. In a preliminary assessment, these compounds were shown to possess activities in the low nM range with the most active being compound 6 with IC values of 2.79 nM against Pf K1 and 3.2 nM against Pf W2. Overall the resistance indices indicate that the compounds have a low potential for cross resistance. Cytotoxicities were determined with Hek293 human embryonic kidney cells and activities against proliferating cells were assessed against A375 human malignant melanoma cells. The selectivity indices of the amino-artemisinin ferrocene derivatives indicate there is overall an appreciably higher selectivity towards the malaria parasite than mammalian cells. 10.1016/j.bmcl.2017.12.057
    Anti-angiogenic properties of artemisinin derivatives (Review). Wei Tianshu,Liu Ju International journal of molecular medicine Angiogenesis, the process involving the development of new blood vessels from existing capillaries, is critical for growth and wound healing. However, pathological angiogenesis contributes to the pathogeneses of numerous diseases, including cancer, rheumatoid arthritis, diabetic retinopathy and macular degeneration. Hence, the inhibition of angiogenesis is an effective therapeutic approach for these diseases. Apart from its anti-malarial properties, artemisinin and its derivatives also exhibit potent anti-angiogenic properties. The molecular mechanisms underlying their inhibitory effects on angiogenesis have been studied by several groups. These investigations have revealed that artemisinins inhibit angiogenesis via the perturbations of cellular signaling pathways involved in the regulation of angiogenesis. Along with a brief introduction to artemisinin derivatives, this review provides a detailed summary of the effects of artemisinins on the mitogen-activated protein kinase (MAPK) pathway, the nuclear factor-κB (NF-κB) pathway and the phosphatidylinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway. Due to the multiplicity of their actions on relevant signaling pathways, artemisinins are promising candidates with potential for use as anti-angiogenic agents for the treatment of related diseases or disorders. 10.3892/ijmm.2017.3085
    Research Progress on Artemisinin and Its Derivatives against Hematological Malignancies. Li Ying,Shan Ning-Ning,Sui Xiao-Hui Chinese journal of integrative medicine Although current therapeutic methods against hematological malignancies are effective in the early stage, they usually lose their effectiveness because of the development of drug resistances. Seeking new drugs with significant therapeutic effects is one of the current research hotspots. Artemisinin, an extract from the plant Artemisia annua Linne, and its derivatives have excellent antimalarial effects in clinical applications as well as excellent safety. Recent studies have documented that artemisinin and its derivatives (ARTs) also have significant effects against multiple types of tumours, including hematological malignancies. This review focuses on the latest research achievements of ARTs in the treatment of hematological malignancies as well as its mechanisms and future applications. The mechanisms of ARTs against different types of hematological malignancies mainly include cell cycle arrest, induction autophagy and apoptosis, inhibition of angiogenesis, production of reactive oxygen species, and induction of differentiation. Additionally, the review also summarizes the anticancer effects of ARTs in many drug-resistant hematological malignancies and its synergistic effects with other drugs. 10.1007/s11655-019-3207-3
    [Artemisinin inhibits proliferation of gallbladder cancer cell lines through triggering cell cycle arrest and apoptosis]. Jia J G,Zhang L G,Guo C X,Wang Y G,Chen B L,Wang Y M,Qian J Zhonghua wai ke za zhi [Chinese journal of surgery] OBJECTIVE:To evaluate the effects of artemisinin on proliferation, cell cycle and apoptosis of gallbladder cancer cells. METHODS:Gallbladder carcinoma cell lines(GBC-SD and NOZ)were cultured in vitro. The effects of artemisinin in different concentration on proliferation of the two cell lines in vitro were examined using MTT assay. The cell cycle distribution of GBC-SD and NOZ cells 24 h after treatments with artemisinin(20 μmol/L) were examined using flow cytometry. The apoptosis of GBC-SD and NOZ cells 24 h after treatments with artemisinin (20 μmol/L) were examined using Annexin V/PI staining.The expressions of p-ERK1/2, CDK4, cyclin D1, p16, cytochrome C and caspase-3 were examined by Western blot assay. t-test and one way ANOVA were used to evaluate the differences between two groups and more than two groups, respectively. RESULTS:The cell proliferation was significantly inhibited by artemisinin, the IC50 of artemisinin against GBC-SD and NOZ cells were 14.05 μmol/L and 12.42 μmol/L, respectively.Artemisinin induced cycle arrest, and G1 population of GBC-SD and NOZ cells increased to 74.60% and 78.86%. Cell apoptosis and apoptotic population of GBC-SD and NOZ cells were increased to 15.67% and 16.51% after dealt with artemisinin, respectively. In addition, expression of p16 was increased, and expressions of p-ERK1/2, CDK4 and cyclin D1 were down-regulated by artemisinin(all P<0.05). Cytochrome C was released from mitochondria to cytoplasm leading to the activation of caspase-3 and PARP after dealt with artemisinin(P<0.05). CONCLUSION:The inhibition effect of artemisinin on the proliferation gallbladder cancer cells is accompanied by down-regulation of ERK1/2 signaling pathway, G1 phase arrest and triggering caspase-3-mediate apoptosis. 10.3760/cma.j.issn.0529-5815.2016.03.014
    Artemisinin suppresses hepatocellular carcinoma cell growth, migration and invasion by targeting cellular bioenergetics and Hippo-YAP signaling. Li Yujie,Lu Jing,Chen Qin,Han Shengnan,Shao Hua,Chen Pingyi,Jin Qiumei,Yang Mingyue,Shangguan Fugen,Fei Mingming,Wang Lu,Liu Yongzhang,Liu Naxin,Lu Bin Archives of toxicology The primary liver cancer (PLC) is one of the leading causes of cancer-related death worldwide. The predominant form of PLC is hepatocellular carcinoma (HCC), which accounts for about 85% of all PLC. Artemisinin (ART) was clinically used as anti-malarial agents. Recently, it was demonstrated to inhibit cell growth and migration in multiple cancer types. However, the molecular mechanism underlying these anti-cancer activity remains largely unknown. Herein, it is discovered that ART dramatically suppresses HCC cell growth in vitro through arresting cell cycle progression, and represses cell migration and invasion via regulating N-cadherin-Snail-E-cadherin axis. In addition, the disruption of cellular bioenergetics contributed to ART-caused cell growth, migration and invasion inhibition. Moreover, ART (100 mg/kg, intraperitoneally) substantially inhibits HCC xenograft growth in vivo. Importantly, Hippo-YAP signal transduction is remarkably inactivated in HCC cells upon ART administration. Collectively, these data reveal a novel mechanism of ART in regulating HCC cell growth, migration, and invasion, which indicates that ART could be considered as a potential drug for the treatment of HCC. 10.1007/s00204-019-02579-3
    From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy. Efferth Thomas Seminars in cancer biology Artemisia annua L. is used throughout Asia and Africa as tea and press juice to treat malaria and related symptomes (fever, chills). Its active ingredient, artemisinin (ARS), has been developed as antimalarial drug and is used worldwide. Interestingly, the bioactivity is not restricted to malaria treatment. We and others found that ARS-type drugs also reveal anticancer in vitro and in vivo. In this review, we give a systematic overview of the literature published over the past two decades until the end of 2016. Like other natural products, ARS acts in a multi-specific manner against tumors. The cellular response of ARS and its derivatives (dihydroartemisinin, artesunate, artemether, arteether) towards cancer cells include oxidative stress response by reactive oxygen species and nitric oxide, DNA damage and repair (base excision repair, homologous recombination, non-homologous end-joining), various cell death modes (apoptosis, autophagy, ferroptosis, necrosis, necroptosis, oncosis), inhibition of angiogenesis and tumor-related signal transduction pathways (e.g. Wnt/β-catenin pathway, AMPK pathway, metastatic pathways, and others) and signal transducers (NF-κB, MYC/MAX, AP-1, CREBP, mTOR etc). ARS-type drugs are at the stairways to the clinics. Several published case reports and pilot phase I/II trials indicate clinical anticancer activity of these compounds. Because of unexpected cases of hepatotoxicity, combinations of ARS-type drugs with complementary and alternative medicines are not recommended, until controlled clinical trials will prove the safety of non-approved combination treatments. 10.1016/j.semcancer.2017.02.009
    Repurposing of artemisinin-type drugs for the treatment of acute leukemia. Lu Xiaohua,Efferth Thomas Seminars in cancer biology Cancer treatment represents an unmet challenge due to the development of drug resistance and severe side effects of chemotherapy. Artemisinin (ARS)-type compounds exhibit excellent antimalarial effects with few side effects and drug-resistance. ARS and its derivatives were also reported to act against various tumor types in vitro and in vivo, including acute leukemia. Therefore, ARS-type compounds may be exquisitely suitable for repurposing in leukemia treatment. To provide comprehensive clues of ARS and its derivatives for acute leukemia treatment, their molecular mechanisms are discussed in this review. Five monomeric molecules and 72 dimers, trimers and hybrids based on the ARS scaffold have been described against acute leukemia. The modes of action involve anti-angiogenic, anti-metastatic and growth inhibitory effects. These properties make ARS-type compounds as potential candidates for the treatment of acute leukemia. Still, more potent and target-selective ARS-type compounds need to be developed. 10.1016/j.semcancer.2020.05.016
    Artemisinin inhibits inflammatory response via regulating NF-κB and MAPK signaling pathways. Wang Ke Si,Li Junbo,Wang Zhe,Mi Chunliu,Ma Juan,Piao Lian Xun,Xu Guang Hua,Li Xuezheng,Jin Xuejun Immunopharmacology and immunotoxicology Artemisinin, isolated from the Chinese plant Artemisia annua, has been used for many years to treat different forms of malarial parasites. In this study, we explored the anti-inflammatory activity of artemisinin and the underlying mechanism of this action. We demonstrated that the anti-inflammatory effects of artemisinin in TPA-induced skin inflammation in mice. Then the artemisinin significantly inhibited the expression of NF-κB reporter gene induced by TNF-α in a dose-dependent manner. Artemisinin also inhibited TNF-α induced phosphorylation and degradation of IκBα, p65 nuclear translocation. Artemisinin also has an impact on upstream signaling of IKK through the inhibition of expression of adaptor proteins, TNF receptor-associated factor 2 (TRAF2) and receptor interacting protein 1 (RIP1). Furthermore, pretreatment of cells with artemisinin prevented the TNF-α-induced expression of NF-κB target genes, such as anti-apoptosis (c-IAP1, Bcl-2, and FLIP), proliferation (COX-2, cyclinD1), invasion (MMP-9), angiogenesis (VEGF), and major inflammatory cytokines (TNF-α, iNOS, and MCP1). We also proved that artemisinin potentiated TNF-α-induced apoptosis. Moreover, artemisinin significantly impaired the ROS production and phosphorylation of p38 and ERK, but did not affect the phosphorylation of JNK. Taken together, artemisinin may be a potentially useful therapeutic agent for inflammatory-related diseases. 10.1080/08923973.2016.1267744
    A fully synthetic 6-aza-artemisinin bearing an amphiphilic chain generates aggregates and exhibits anti-cancer activities. Koi Hikari,Takahashi Norihito,Fuchi Yasufumi,Umeno Tomohiro,Muramatsu Yukiko,Seimiya Hiroyuki,Karasawa Satoru,Oguri Hiroki Organic & biomolecular chemistry Installation of a nitrogen at the C6 position of artemisinin facilitates the addition of a functional unit on the cyclohexane moiety (C-ring). In this study, conjugation of an amphiphilic chain, composed of sequentially connected hydrophilic oligoethylene glycol, hydrophobic alkyl chain, urea, and 4,4'-disubstituted biphenyl linker, imparted self-assembling properties. The fully synthetic mid-molecular weight 6-aza-artemisinin 6 bearing the amphiphilic moiety formed aggregates (approx. 200 nm) at ambient temperature and exhibited increased in vitro anti-cancer activities compared to the N-benzylated aza-artemisinin 5. 10.1039/d0ob00919a
    Artemisinin and its derivatives can significantly inhibit lung tumorigenesis and tumor metastasis through Wnt/β-catenin signaling. Tong Yunli,Liu Yuting,Zheng Hongming,Zheng Liang,Liu Wenqin,Wu Jinjun,Ou Rilan,Zhang Guiyu,Li Fangyuan,Hu Ming,Liu Zhongqiu,Lu Linlin Oncotarget Non-small-cell lung cancer (NSCLC) is the most prevalent malignancy worldwide given its high incidence, considerable mortality, and poor prognosis. The anti-malaria compounds artemisinin (ART), dihydroartemisinin (DHA), and artesunate (ARTS) reportedly have anti-cancer potential, although the underlying mechanisms remain unclear. In this work, we used flow cytometry to show that ART, DHA, and ARTS could inhibit the proliferation of A549 and H1299 cells by arresting cell cycle in G1 phase. Meanwhile, tumor malignancy including migration, invasion, cancer stem cells, and epithelial-mesenchymal transition were also significantly suppressed by these compounds. Furthermore, ART, DHA, and ARTS remarkably decreased tumor growth in vivo. By using IWP-2, the inhibitor of Wnt/β-catenin pathway, and Wnt5a siRNA, we found that ART, DHA, and ARTS could render tumor inhibition partially dependent on Wnt/β-catenin inactivation. These compounds could strikingly decrease the protein level of Wnt5-a/b and simultaneously increase those of NKD2 and Axin2, ultimately resulting in β-catenin downregulation. In summary, our findings revealed that ART, DHA, and ARTS could suppress lung-tumor progression by inhibiting Wnt/β-catenin pathway, thereby suggesting a novel target for ART, DHA, and ARTS in cancer treatment. 10.18632/oncotarget.8920
    Design, synthesis and pharmacological evaluation of novel Artemisinin-Thymol. Natural product research A molecular hybridization of natural products is a new concept in drug discovery and having critical roles to design new molecules with improved biological properties. Hybrid molecules display higher biological activities when compared to the parent drugs. In the present study, two natural products (thymol and artemisinin ()) are used for the synthesis of new hybrid thymol-artemisinin. After characterization, the cytotoxic activity of was tested against different cancer cell lines and non-cancerous human cell line. show the cytotoxic effect with EC values 70,96μM for HepG2, 97,31μM for LnCap, 6,03μM for Caco-2, 77,98μM for HeLa and 62,28μM for HEK293 cells, respectively. Moreover, was checked for drug-likeness, and the kinase inhibitory activity. is investigated by using molecular docking. The results of qPCR was indicated CDK2 and P38 were inhibited by . These results improved that thymol-artemisinin may be new candidates as an anticancer agents. 10.1080/14786419.2020.1865954
    Artemisinin-Loaded Mesoporous Nanoplatform for pH-Responsive Radical Generation Synergistic Tumor Theranostics. Liu Lidong,Liu Yuxin,Ma Liyi,Mao Fang,Jiang Anqi,Liu Dongdong,Wang Lu,Jia Qi,Zhou Jing ACS applied materials & interfaces The development of novel and effective cancer treatments will greatly contribute to prolonging and improving patient lives. In this study, a multifunctional nanoplatform was designed and developed based on mesoporous NiO (mNiO) nanoparticles and terbium complexes as an artemisinin (ART) vehicle, a T-weighted contrast agent, and a luminescence imaging probe. mNiO is a novel pH-responsive material that can degrade and release nickel ions (Ni) in an acidic tumor microenvironment. The endoperoxide bridge bond in the structure of ART tends to react with Ni to produce radicals that can kill tumor cells. On the basis of its excellent near-infrared absorbance, mNiO can also be considered as a novel photothermal conversion agent for cancer photothermal therapy (PTT). Compared with free ART or PTT only, this novel agent showed remarkably enhanced antitumor activity in cultured cells and in tumor mice models, owing to the hypoxic tumor microenvironment impelling synergistic therapeutic action. These results provide a novel way of using a promising natural drug-based nanoplatform for synergistic therapy of tumors. 10.1021/acsami.7b18320
    [Research progress of effect of artemisinin family drugs on T lymphocytes immunomodulation]. Yan Si-Chao,Li Yu-Jie,Wang Ya-Jie,Cai Wei-Yan,Weng Xiao-Gang,Li Qi,Chen Ying,Yang Qing,Zhu Xiao-Xin Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica Artemisinin was isolated from traditional Chinese herb Artemisia annua for treating malaria. A series of derivatives,like dihydroartemisinin,artesunate,artemether,artether,had the same core chemical structure,and sesquiterpene lactone containing peroxide bridge constitute the basic chemical structure. Besides anti-malaria,artemisinin family drugs were found to ameliorate many different diseases,which have attracted wide attention in recent years. Among different diseases,artemisinin family drugs were found to have T lymphocytes immunomodulation effects,including activation,proliferation,differentiation,apoptosis and subsets function. Because T cell immunologic response is the key point of many diseases,and impact the pathogenic process,therapeutic effect and prognosis,the drug studies with it as the target have become hotspots in recent years. Studies of artemisinin family drug on T cell immunomodulation were still at the initial stage and involved in different disease; furthermore,T cell immune process involves complicated molecular mechanism,it is imperative to summarize the advance of current studies for further systematic explanation and exploration of their characteristics and mechanisms. This article will summarize the research progress of artemisinin family drugs for malaria,autoimmune disease,hypersensitivity reaction,tumor,schistosomiasis and AIDS relating to T cell immune modulation,so as to provide basic and professional reference for related research and application. 10.19540/j.cnki.cjcmm.20190618.401
    Synthesis, antimalarial activities and cytotoxicities of amino-artemisinin-1,2-disubstituted ferrocene hybrids. de Lange Christo,Coertzen Dina,Smit Frans J,Wentzel Johannes F,Wong Ho Ning,Birkholtz Lyn-Marie,Haynes Richard K,N'Da David D Bioorganic & medicinal chemistry letters Artemisinin-ferrocene conjugates incorporating a 1,2-disubstituted ferrocene analogous to that embedded in ferroquine but attached via a piperazine linker to C10 of the artemisinin were prepared from the piperazine artemisinin derivative, and activities were evaluated against asexual blood stages of chloroquine (CQ) sensitive NF54 and CQ resistant K1 and W2 strains of Plasmodium falciparum (Pf). The most active was the morpholino derivative 5 with IC of 0.86 nM against Pf K1 and 1.4 nM against Pf W2. The resistance indices were superior to those of current clinical artemisinins. Notably, the compounds were active against Pf NF54 early and late blood stage gametocytes - these exerted >86% inhibition at 1 µM against both stages; they are thus appreciably more active than methylene blue (∼57% inhibition at 1 µM) against late stage gametocytes. The data portends transmission blocking activity. Cytotoxicity was determined against human embryonic kidney cells (Hek293), while human malignant melanoma cells (A375) were used to assess their antitumor activity. 10.1016/j.bmcl.2018.08.037
    The selectivity of artemisinin-based drugs on human lung normal and cancer cells. Li Xinyang,Gu Shiyan,Sun Donglei,Dai Huangmei,Chen Hongyu,Zhang Zunzhen Environmental toxicology and pharmacology Artemisinin-based drugs are documented to possess anticancer potential that is selectively effective to cancer cells. However, this selectivity is disputable in different studies and the mechanism is still unclear. To clarify this discrepancy, this study employed five assays to evaluate the cytotoxic effects of artemisinin and artesunate on normal human bronchial epithelial (HBE) cells and lung adenocarcinoma A549 cells. The results of five cytotoxic assays coherently showed that artemisinin and artesunate caused dose-dependent cytotoxicity in both HBE and A549 cells with a slight selectivity to A549 cells. Further, both HBE cells and A549 cells demonstrated elevated levels of intracellular reactive oxygen species (ROS) and increased DNA damage. Since artemisinin and artesunate exerted significant cytotoxic effect on both normal cells and cancer cells via the same pathway of ROS-mediated DNA damage, the side effects of artemisinin and artesunate on normal cell cannot be ignored when developing their antitumor effects. 10.1016/j.etap.2017.12.004
    Effects of artemisinin on proliferation and apoptosis of human liver cancer HepG2 cells: A protocol of systematic review and meta-analysis. Medicine BACKGROUND:This study will examine the effects of artemisinin on proliferation and apoptosis of human liver cancer HepG2 cells (HLCHG-2C). METHODS:This study will systematically retrieve potential literatures in MEDLINE, Scopus, Web of Science, Cochrane Library, EMBASE, WANGFANG, and China National Knowledge Infrastructure from their initiation to the February 29, 2020. There are not limitations related to the language and publication time. All case-controlled studies (CCSs) or randomized controlled studies (RCSs) will be included in this study which investigated the effects of artemisinin on proliferation and apoptosis of HLCHG-2C. Two independent investigators will examine searched records, collect data from included studies, and will identify their methodological quality. Any divergences will be disentangled by discussion with another investigator. RevMan 5.3 software will be placed to pool the data and to carry out data analysis. RESULTS:This study will summarize all eligible studies to test the effects of artemisinin on proliferation and apoptosis of HLCHG-2C. CONCLUSION:The results of this study will exert evidence to examine the effects of artemisinin on proliferation and apoptosis of HLCHG-2C, and it may benefit further research, patients, and healthcare providers. SYSTEMATIC REVIEW REGISTRATION:INPLASY202040075. 10.1097/MD.0000000000020290
    Targeting Inhibition of Accumulation and Function of Myeloid-Derived Suppressor Cells by Artemisinin via PI3K/AKT, mTOR, and MAPK Pathways Enhances Anti-PD-L1 Immunotherapy in Melanoma and Liver Tumors. Journal of immunology research Despite the remarkable success and efficacy of immune checkpoint blockade (ICB) therapy such as anti-PD-L1 antibody in treating cancers, myeloid-derived suppressor cells (MDSCs) that lead to the formation of the protumor immunosuppressive microenvironment are one of the major contributors to ICB resistance. Therefore, inhibition of MDSC accumulation and function is critical for further enhancing the therapeutic efficacy of anti-PD-L1 antibody in a majority of cancer patients. Artemisinin (ART), the most effective antimalarial drug with tumoricidal and immunoregulatory activities, is a potential option for cancer treatment. Although ART is reported to reduce MDSC levels in 4T1 breast tumor model and improve the therapeutic efficacy of anti-PD-L1 antibody in T cell lymphoma-bearing mice, how ART influences MDSC accumulation, function, and molecular pathways as well as MDSC-mediated anti-PD-L1 resistance in melanoma or liver tumors remains unknown. Here, we reported that ART blocks the accumulation and function of MDSCs by polarizing M2-like tumor-promoting phenotype towards M1-like antitumor one. This switch is regulated via PI3K/AKT, mTOR, and MAPK signaling pathways. Targeting MDSCs by ART could significantly reduce tumor growth in various mouse models. More importantly, the ART therapy remarkably enhanced the efficacy of anti-PD-L1 immunotherapy in tumor-bearing mice through promoting antitumor T cell infiltration and proliferation. These findings indicate that ART controls the functional polarization of MDSCs and targeting MDSCs by ART provides a novel therapeutic strategy to enhance anti-PD-L1 cancer immunotherapy. 10.1155/2022/2253436
    Synthesis of artemisinin-piperazine-furan ether hybrids and evaluation of in vitro cytotoxic activity. Wei Meng-Xue,Yu Jia-Ying,Liu Xin-Xin,Li Xue-Qiang,Zhang Meng-Wei,Yang Pei-Wen,Yang Jin-Hui European journal of medicinal chemistry For the first time, eight novel artemisinin-piperazine-furane ether hybrids (5a-h) were efficiently synthesized and investigated for their in vitro cytotoxic activity against some human cancer and benign cells. The absolute configuration of hybrid 5c was determined by X-ray crystallographic analysis. Hybrids 5a-h exhibited more pronounced growth-inhibiting action on hepatocarcinoma cell lines than their parent dihydroartemisinin (DHA) and the reference cytosine arabinoside (ARA). The hybrid 5a showed the best cytotoxic activity against human hepatocarcinoma cells SMMC-7721 (IC = 0.26 ± 0.03 μM) after 24 h. Furthermore, hybrid 5a also showed good cytotoxic activity against human breast cancer cells MCF-7 and low cytotoxicity against human breast benign cells MCF-10A in vitro. We found the cytotoxicity of hybrid 5a did not change when tumour cells absorb iron sulfate (FeSO); thus, we conclude the anti-tumour mechanism induced by iron ions (Fe) is unclear. 10.1016/j.ejmech.2021.113295
    Synthesis and evaluation of cytotoxic activities of artemisinin derivatives. Sun Qian,Wang Jin,Li Yao,Zhuang Jingjing,Zhang Qian,Sun Xiao,Sun Dequn Chemical biology & drug design Artemisinin is a naturally occurring antimalarial agent which has shown potent anticancer activity. In this work, new artemisinin derivatives with the piperazine group were synthesized. The cytotoxic activities of derivatives 5a-5d were evaluated by MTT assay against ten cell lines. The results showed that 5a-5d were more effective in inhibiting cancer cell growth than artemisinin. 5d was the most active against HepG2 and PLC-PRF-5 cells and presented no cytotoxicity on L-02 cells. Hoechst 33342 staining and flow cytometry experiment revealed that 5d could induce HepG2 and PLC-PRF-5 cell apoptosis. Flow cytometry analysis showed that 5d induced the loss of mitochondrial membrane potential (MMP) and increased the levels of intracellular free calcium and reactive oxygen species. 5d also induced cell cycle arrest in G2/M phase in HepG2 cells. According to the results of Western blotting and caspase-3 kit, 5d could significantly increase the content of p53, bax, Apaf-1, and caspase-3 and decrease the protein level of bcl-2, pro-caspase-9, and pro-caspase-3 in HepG2 cells. These findings indicate that 5d activates the mitochondria-mediated apoptotic pathway in HepG2 cells and may merit further investigation as a potential therapeutic agent for hepatocellular carcinoma. 10.1111/cbdd.13016
    Resveratrol and artemisinin eudragit-coated liposomes: A strategy to tackle intestinal tumors. Caddeo Carla,Gabriele Morena,Nácher Amparo,Fernàndez-Busquets Xavier,Valenti Donatella,Maria Fadda Anna,Pucci Laura,Manconi Maria International journal of pharmaceutics Resveratrol and artemisinin, two naturally occurring compounds with a wide range of biological activities, have been reported to exert antitumor effects against several types of cancer. In this work, Eudragit-coated liposomes were developed to safely transport resveratrol and artemisinin through the gastrointestinal tract and target the intestine. The physico-chemical properties of the Eudragit-coated liposomes were assessed by light scattering and cryogenic transmission electron microscopy. Nanosized (around 100 nm), spherical or elongated, unilamellar vesicles were produced. The protective effect of the Eudragit coating was confirmed by assessing the physical stability of the vesicles in fluids mimicking the gastrointestinal environment. Furthermore, the vesicles were found to exert a pro-oxidant activity in intestinal adenocarcinoma cells, which resulted in a marked mortality due to the generation of reactive oxygen species (ROS). A time- and dose-dependent cell growth inhibitory effect was detected, with elevated ROS levels when resveratrol and artemisinin were combined. Therefore, the proposed formulations may represent a valuable means to counteract intestinal tumor growth. 10.1016/j.ijpharm.2020.120083
    Artemisinin as a Chinese medicine, selectively induces apoptosis in pancreatic tumor cell line. Noori Shokoofe,Hassan Zuhair M,Farsam Vida Chinese journal of integrative medicine OBJECTIVE:To investigate the possible mechanism through which Artemisinin induced apoptosis in pancreatic cell line. METHODS:Column chromatography, thin layer chromatography (TLC) and proton NMR spectroscopy were used to purify Artemisinin. The flowcytometry was employed to detect apoptosis and reactive oxygen species (ROS). RESULTS:The results indicated that 50% inhibiting concentration (IC50 value) for pancreatic cell line (RIN) was 45 μmol/L of Artemisinin. Artemisinin had no cytotoxic effect on the growth of peripheral blood lymphocytes. The mechanism of apoptosis was evaluated by measuring intracellular ROS. It was shown that Artemisinin-induced apoptosis occurred independently of the binding of CD95L to CD95 receptor in the RIN cells. Moreover, Artemisinin, in a dose-dependent manner, could significantly increase the level of ROS. CONCLUSION:Artemisinin can induce apoptosis in the RIN cells via the generation of ROS and triggering the intrinsic pathway of cell death. 10.1007/s11655-013-1454-2
    Discovery of novel artemisinin-sulfonamidehybrids as potential carbonicanhydraseIX inhibitors with improved antiproliferative activities. An Ran,Lin Bin,Zhao Shuang,Cao Chun,Wang Yuanxin,Cheng Xue,Liu Yichuang,Guo Mengbi,Xu Hang,Wang Yitong,Hou Zhuang,Guo Chun Bioorganic chemistry A series of artemisinin-sulfonamide hybrids (1-16) have been designed and synthesized by using molecular hybridization approach and investigated for the inhibitory activity of four human (h) carbonic anhydrases (CAs, EC 4.2.1.1), hCA I, II, IX and XII. The results indicated most of the target compounds showed better CA IX and CA XII inhibitory activity than the starting segment sulfanilamide. Among all the compounds, compound 3 (IC: 5 nM) showed the best CA IX inhibitory efficacy. The p-aminobenzenesulfonamide derivatives showed significant antiproliferative activities against MDA-MB-231 breast cancer cell line and HT-29 colon cancer cell line under hypoxic conditions where CA IX and CA XII are overexpressed and most of them showed no apparent cytotoxic effects toward MCF-10A normal mammary epithelial cell. Among these derivatives, compound 3 displayed the most potent antiproliferative activities (IC: 0.65 μM) against HT-29 cell line under hypoxia and low cytotoxicity (IC: 78.0 μM) toward normal cell line. Meanwhile, compound 3 was found to efficiently decrease the hypoxia-induced extracellular acidification in both cancer cells. Molecular docking studies of compounds 3, 4, 5 and 9 revealed the proper interactions between the hybrid molecules and the active site of CA IX. All the results proved the effectiveness of the hybridization approach to develop novel artemisinin-sulfonamide compounds targeting CA IX for cancer treatment. 10.1016/j.bioorg.2020.104347
    Design and synthesis of novel artemisinin derivatives with potent activities against colorectal cancer in vitro and in vivo. Wang Liang-Liang,Kong Lingmei,Liu Hui,Zhang Yunqin,Zhang Li,Liu Xingyong,Yuan Feng,Li Yan,Zuo Zhili European journal of medicinal chemistry A series of novel derivatives of artemisinin-4-(arylamino)quinazoline have been designed and synthesized, and most of them showing potent in vitro cytotoxic activity against HCT116 and WM-266-4 cell lines. Compound 32 was the most active derivative against HCT116 cell line with an IC of 110 nM, and significantly improved the antitumor activity of the parent compounds dihydroartemisinin (DHA) (IC = 2.85 μM) and Gefitinib (IC = 19.82 μM). In vivo HCT116 xenografts assay showed that compound 32 exhibited potent antitumor activity with obvious tumor growth delay and tumor shrunken after 18 days treatment on xenografted mice, and especially without loss of body weight. Our results indicate that compounds 32 may represent a safe, novel structural lead for developing new chemotherapy of colorectal cancer. 10.1016/j.ejmech.2019.111665
    Synthesis and biological evaluation of a series of non-hemiacetal ester derivatives of artemisinin. Zuma Nonkululeko H,Smit Frans J,de Kock Carmen,Combrinck Jill,Smith Peter J,N'Da David D European journal of medicinal chemistry In an attempt to improve the efficacy and stability of current, clinically used artemisinins, a series non-hemiacetal ester derivatives of artemisinin were synthesized and evaluated for their in vitro antiplasmodial and anticancer activities as well as cytotoxicities. These esters were synthesized through the reaction of acid anhydrides, or acid chlorides with artemisinin derived alcohol. In vitro antiplasmodial activity assessments were conducted against intraerythrocytic NF54 and Dd2 Plasmodium falciparum strains. Cytotoxicities were assessed, using normal human fetal lung fibroblast (WI-38) and Chinese hamster ovarian (CHO) mammalian cell lines, while anticancer activities were tested by using panels with three cell lines, consisting of renal (TK10), melanoma (UACC62) and breast (MCF7) cancer cells. Most compounds were found active against the breast cancer cell line. Since antiplasmodial activities for most compounds were found comparable only to that of artesunate, this study did not yield any esters with significantly improved antimalarial efficacies, nor did it deliver any promising antitumor hits. However, from the outcomes of this study, compounds with good safety profiles and increased thermal stabilities, compared to the clinically used artemisinins, were identified. The benzoate derivative 11 was found to have antimalarial activity, comparable to that of dihydroartemisinin and was it subsequently identified as a candidate for further investigation in the urgent search for new, safe and effective antimalarial drugs. 10.1016/j.ejmech.2016.07.027
    Combination treatment with artemisinin and oxaliplatin inhibits tumorigenesis in esophageal cancer EC109 cell through Wnt/β-catenin signaling pathway. Wang Tao,Wang Jian,Ren Wei,Liu Zhu-Long,Cheng Yu-Feng,Zhang Xiao-Mei Thoracic cancer BACKGROUND:Esophageal cancer (EC) is a prevalent malignant cancer worldwide. Interestingly, the antimalaria compound artemisinin (ART) is also reported to have anticancer potential, although its underlying mechanism in EC is unclear. In this study, we explored the anticancer role of ART in EC109 and further explored the combination of ART and oxaliplatin (OXA) for their synergetic anticancer functions. METHODS:Human EC cell line EC109 was used. After ART or oxaliplatin (OXA) treatment, cell proliferation, migration, and invasion were measured by MTT, transwell, and scratch wound assays, respectively. Flow cytometry was performed to examine the cell cycle and apoptosis. The mRNA and protein levels were determined using qRT-PCR and western blotting. RESULTS:The migration and invasion abilities of EC109 were suppressed by ART. This was due to the inhibitory effect of ART on the Wnt/β-catenin signaling pathway. The levels of β-catenin, c-myc, and survivin were also downregulated by ART. ART inhibits the proliferation of EC109 cells by arresting the cells in the G1-phase of cell cycle. By using LiCl, an activator of the Wnt/β-catenin pathway, we further verified that the inhibition of the Wnt/β-catenin pathway was indeed due to ART. Remarkably, ART enhanced the anticancer effects of OXA in EC109 cells. OXA combined with ART was found to be more efficient in decreasing tumor growth compared to the individual drugs. CONCLUSIONS:ART could suppress tumor progression by inhibiting Wnt/β-catenin signaling pathway, and it may also enhance the antitumor effect of OXA in EC. Thus, ART could be a novel anticancer drug for EC treatment. KEY POINTS:SIGNIFICANT FINDINGS OF THE STUDY: ART could be a novel anticancer drug for esophageal cancer (EC) treatment. WHAT THIS STUDY ADDS:Combination treatment with artemisinin and oxaliplatin inhibits tumorigenesis in esophageal cancer EC109 cells through the Wnt/β-catenin signaling pathway. 10.1111/1759-7714.13570
    Novel artemisinin derivative FO8643 with anti-angiogenic activity inhibits growth and migration of cancer cells via VEGFR2 signaling. European journal of pharmacology The vascular endothelial growth factor receptor 2 (VEGFR2) is widely recognized as a key effector in angiogenesis and cancer progression and has been considered a critical target for the development of anti-cancer drugs. Artemisinin (ARS) and its derivatives exert profound efficacy in treating not only malaria but also cancer. As a novel ARS-type compound, FO8643 caused significant suppression of the growth of a panel of cancer cells, including both solid and hematologic malignancies. In CCRF-CEM leukemia cells, FO8643 dramatically inhibited cell proliferation coupled with increased apoptosis and cell cycle arrest. Additionally, FO8643 restrained cell migration in the 2D wound healing assay as well as in a 3D spheroid model of human hepatocellular carcinoma HUH-7 cells. Importantly, SwissTargetPrediction predicted VEGFR2 as an underlying target for FO8643. Molecular docking simulation further indicated that FO8643 formed hydrogen bonds and hydrophobic interactions within the VEGFR2 kinase domain. Moreover, FO8643 directly inhibited VEGFR2 kinase activity and its downstream action including MAPK and PI3K/Akt signaling pathways in HUH-7 cells. Encouragingly, FO8643 decreased angiogenesis in the chorioallantoic membrane assay in vivo. Collectively, FO8643 is a novel ARS-type compound exerting potential VEGFR2 inhibition. FO8643 may be a viable drug candidate in cancer therapy. 10.1016/j.ejphar.2022.175158
    Artemisinin derivatives inactivate cancer-associated fibroblasts through suppressing TGF-β signaling in breast cancer. Yao Yuyuan,Guo Qinglong,Cao Yue,Qiu Yangmin,Tan Renxiang,Yu Zhou,Zhou Yuxin,Lu Na Journal of experimental & clinical cancer research : CR BACKGROUND:Cancer-associated fibroblasts (CAFs) are activated fibroblasts associated with cancer. They have an important role in tumor growth and metastasis. Artemisinin (ART) is a sesquiterpene lactone extracted from Chinese herb qinghao, and artemether (ARM), artesunate (ARS) and dihydroartemisinin (DHA) were synthesized derivatives of artemisinin, which also have anti-malarial and anti-cancer effects such as artemisinin. METHODS:In this study, we investigated the in-vitro and in-vivo effects of artemisinin derivatives on inactivating cancer-associated fibroblasts and uncovered its underlying mechanism. RESULTS:We demonstrated that ARS and DHA could revert L-929-CAFs and CAFs from activated to inactivated state in vitro. Mechanically, ARS and DHA could suppress TGF-β signaling to inhibit activation of L-929-CAFs and CAFs, and decreased interaction between tumor and tumor microenvironment. The results showed that ARS and DHA could suppress CAFs-induced breast cancer growth and metastasis in the orthotopic model. Conformably, ARS and DHA suppressed TGF-β signaling to inactivate cancer-associated fibroblasts and inhibit cancer metastasis in vivo. CONCLUSIONS:Artemisinin derivatives are potential therapeutic agents for the treatment of breast cancer. 10.1186/s13046-018-0960-7
    Artemisinin disrupts androgen responsiveness of human prostate cancer cells by stimulating the 26S proteasome-mediated degradation of the androgen receptor protein. Steely Andrea M,Willoughby Jamin A,Sundar Shyam N,Aivaliotis Vasiliki I,Firestone Gary L Anti-cancer drugs Androgen receptor (AR) expression and activity is highly linked to the development and progression of prostate cancer and is a target of therapeutic strategies for this disease. We investigated whether the antimalarial drug artemisinin, which is a sesquiterpene lactone isolated from the sweet wormwood plant Artemisia annua, could alter AR expression and responsiveness in cultured human prostate cancer cell lines. Artemisinin treatment induced the 26S proteasome-mediated degradation of the receptor protein, without altering AR transcript levels, in androgen-responsive LNCaP prostate cancer cells or PC-3 prostate cancer cells expressing exogenous wild-type AR. Furthermore, artemisinin stimulated AR ubiquitination and AR receptor interactions with the E3 ubiquitin ligase MDM2 in LNCaP cells. The artemisinin-induced loss of AR protein prevented androgen-responsive cell proliferation and ablated total AR transcriptional activity. The serine/threonine protein kinase AKT-1 was shown to be highly associated with artemisinin-induced proteasome-mediated degradation of AR protein. Artemisinin treatment activated AKT-1 enzymatic activity, enhanced receptor association with AKT-1, and induced AR serine phosphorylation. Treatment of LNCaP cells with the PI3-kinase inhibitor LY294002, which inhibits the PI3-kinase-dependent activation of AKT-1, prevented the artemisinin-induced AR degradation. Furthermore, in transfected receptor-negative PC-3 cells, artemisinin failed to stimulate the degradation of an altered receptor protein (S215A/S792A) with mutations in its two consensus AKT-1 serine phosphorylation sites. Taken together, our results indicate that artemisinin induces the degradation of AR protein and disrupts androgen responsiveness of human prostate cancer cells, suggesting that this natural compound represents a new potential therapeutic molecule that selectively targets AR levels. 10.1097/CAD.0000000000000547
    Artemisinin Attenuated Hydrogen Peroxide (HO)-Induced Oxidative Injury in SH-SY5Y and Hippocampal Neurons via the Activation of AMPK Pathway. Zhao Xia,Fang Jiankang,Li Shuai,Gaur Uma,Xing Xingan,Wang Huan,Zheng Wenhua International journal of molecular sciences Oxidative stress is believed to be one of the main causes of neurodegenerative diseases such as Alzheimer's disease (AD). The pathogenesis of AD is still not elucidated clearly but oxidative stress is one of the key hypotheses. Here, we found that artemisinin, an anti-malarial Chinese medicine, possesses neuroprotective effects. However, the antioxidative effects of artemisinin remain to be explored. In this study, we found that artemisinin rescued SH-SY5Y and hippocampal neuronal cells from hydrogen peroxide (HO)-induced cell death at clinically relevant doses in a concentration-dependent manner. Further studies showed that artemisinin significantly restored the nuclear morphology, improved the abnormal changes in intracellular reactive oxygen species (ROS), reduced the mitochondrial membrane potential, and caspase-3 activation, thereby attenuating apoptosis. Artemisinin also stimulated the phosphorylation of the adenosine monophosphate -activated protein kinase (AMPK) pathway in SH-SY5Y cells in a time- and concentration-dependent manner. Inhibition of the AMPK pathway attenuated the protective effect of artemisinin. These data put together suggested that artemisinin has the potential to protect neuronal cells. Similar results were obtained in primary cultured hippocampal neurons. Cumulatively, these results indicated that artemisinin protected neuronal cells from oxidative damage, at least in part through the activation of AMPK. Our findings support the role of artemisinin as a potential therapeutic agent for neurodegenerative diseases. 10.3390/ijms20112680
    The Effects of Artemisinin on the Cytolytic Activity of Natural Killer (NK) Cells. Houh Youn Kyung,Kim Kyung Eun,Park Sunyoung,Hur Dae Young,Kim Seonghan,Kim Daejin,Bang Sa Ik,Yang Yoolhee,Park Hyun Jeong,Cho Daeho International journal of molecular sciences Artemisinin, a chemical compound used for the treatment of malaria, has been known to show anti-cancer activity. However, the effect of this chemical on natural killer (NK) cells, which are involved in tumor killing, remains unknown. Here, we demonstrate that artemisinin exerts a potent anti-cancer effect by activating NK cells. NK-92MI cells pre-treated with artemisinin were subjected to a cytotoxicity assay using K562 cells. The results showed that artemisinin significantly enhances the cytolytic activity of NK cells in a dose-dependent manner. Additionally, the artemisinin-enhanced cytotoxic effect of NK-92MI cells on tumor cells was accompanied by the stimulation of granule exocytosis, as evidenced by the detection of CD107a expression in NK cells. Moreover, this enhancement of cytotoxicity by artemisinin was also observed in human primary NK cells from peripheral blood. Our results suggest that artemisinin enhances human NK cell cytotoxicity and degranulation. This is the first evidence that artemisinin exerts antitumor activity by enhancing NK cytotoxicity. Therefore, these results provide a deeper understanding of the action of artemisinin and will contribute to the development and application of this class of compounds in cancer treatment strategies. 10.3390/ijms18071600
    Artemisinin inhibits tumour necrosis factor-α-induced vascular smooth muscle cell proliferation in vitro and attenuates balloon injury-induced neointima formation in rats. Cao Qian,Jiang Yan,Shi Jin,Liu Xue,Chen Jie,Niu Tiesheng,Li Xiaodong Clinical and experimental pharmacology & physiology The aim of this study was to evaluate the effect of artemisinin (ART) on rat vascular smooth muscle cell (VSMC) proliferation induced by tumour necrosis factor (TNF)-α, cell cycle arrest, and apoptosis, and its effect on neointima formation after balloon injury of rat carotid artery. Primary rat VSMC were identified by immunofluorescence assay. The proliferation of VSMC induced by TNF-α was significantly inhibited by ART treatment in a dose-dependent manner. Treatment with 100-μM ART significantly reduced the expression of proliferating cell nuclear antigen. In contrast, the same treatment arrested the cell cycle in G0/G1 phase. Western blot analysis showed that the cell cycle-related proteins cyclin D1, cyclin E, cyclin-dependent kinase 2, and cyclin-dependent kinase 4 were downregulated by ART in TNF-α-stimulated VSMC. For apoptosis induced by ART, cleaved caspase-3/-9 was detected, and the pro-apoptotic protein Bcl-2-associated X protein was upregulated while the anti-apoptotic protein Bcl-2 was downregulated. The results suggest that ART can effectively inhibit the proliferation of VSMC induced by TNF-α through the apoptotic induction pathway and cell cycle arrest. Also, balloon injury indicated that ART significantly inhibited neointima formation in the rat carotid arteries. 10.1111/1440-1681.12375
    Artemisinin derivatives induce iron-dependent cell death (ferroptosis) in tumor cells. Ooko Edna,Saeed Mohamed E M,Kadioglu Onat,Sarvi Shabnam,Colak Merve,Elmasaoudi Kaoutar,Janah Rabab,Greten Henry J,Efferth Thomas Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:Apoptosis and other forms of cell death have been intensively investigated in the past years to explain the mode of action of synthetic anticancer drugs and natural products. Recently, a new form of cell death emerged, which was termed ferroptosis, because it depends on intracellular iron. Here, the role of genes involved in iron metabolism and homeostasis for the cytotoxicity of ten artemisinin derivatives have been systematically investigated. MATERIAL AND METHODS:Log10IC50 values of 10 artemisinin derivatives (artesunate, artemether, arteether, artenimol, artemisitene, arteanuin B, another monomeric artemisinin derivative and three artemisinin dimer molecules) were correlated to the microarray-based mRNA expression of 30 iron-related genes in 60 cell lines of the National Cancer Institute (NCI, USA) as determined in 218 different microarray hybridization experiments. The effect of desferoxamine and ferrostatin-1 on the cytotoxicity of artenimol of CCRF-CEM cells was determined by resazurin assays. The mRNA expression of TFRC was exemplarily validated by immunohistochemical detection of transferrin receptor protein expression. RESULTS:The mRNA expression of 20 genes represented by 59 different cDNA clones significantly correlated to the log10IC50 values for the artemisinins, including genes encoding transferrin (TF), transferrin receptors 1 and 2 (TFRC, TFR2), cerulopasmin (CP), lactoferrin (LTF) and others. The ferroptosis inhibitor ferrostatin-1 and the iron chelator deferoxamine led to a significantly reduced cytotoxicity of artenimol, indicating ferroptosis as cell death mode. CONCLUSION:The numerous iron-related genes, whose expression correlated with the response to artemisinin derivatives speak in factor for the relevance of iron for the cytotoxic activity of these compounds. Treatment with ferroptosis-inducing agents such as artemisinin derivatives represents an attractive strategy for cancer therapy. Pre-therapeutic determination of iron-related genes may indicate tumor sensitivity to artemisinins. Ferroptosis induced by artemisinin-type drugs deserve further investigation for individualized tumor therapy. 10.1016/j.phymed.2015.08.002
    Characterization of the Artemisinin Binding Site for Translationally Controlled Tumor Protein (TCTP) by Bioorthogonal Click Chemistry. Li Weichao,Zhou Yiqing,Tang Guanghui,Xiao Youli Bioconjugate chemistry Despite the fact that multiple artemisinin-alkylated proteins in Plasmodium falciparum have been identified in recent studies, the alkylation mechanism and accurate binding site of artemisinin-protein interaction have remained elusive. Here, we report the chemical-probe-based enrichment of the artemisinin-binding peptide and characterization of the artemisinin-binding site of P. falciparum translationally controlled tumor protein (TCTP). A peptide fragment within the N-terminal region of TCTP was enriched and found to be alkylated by an artemisinin-derived probe. MS2 fragments showed that artemisinin could alkylate multiple amino acids from Phe12 to Tyr22 of TCTP, which was supported by labeling experiments upon site-directed mutagenesis and computational modeling studies. Taken together, the "capture-and-release" strategy affords consolidated advantages previously unavailable in artemisinin-protein binding site studies, and our results deepened the understanding of the mechanism of protein alkylation via heme-activated artemisinin. 10.1021/acs.bioconjchem.6b00556
    Artemisinin-type drugs for the treatment of hematological malignancies. Mancuso R I,Foglio M A,Olalla Saad S T Cancer chemotherapy and pharmacology Qinghaosu, known as artemisinin (ARS), has been for over two millennia, one of the most common herbs prescribed in traditional Chinese medicine (TCM). ARS was developed as an antimalarial drug and currently belongs to the established standard treatments of malaria as a combination therapy worldwide. In addition to the antimalarial bioactivity of ARS, anticancer activities have been shown both in vitro and in vivo. Like other natural products, ARS acts in a multi-specific manner also against hematological malignancies. The chemical structure of ARS is a sesquiterpene lactone, which contains an endoperoxide bridge essential for activity. The main mechanism of action of ARS and its derivatives (artesunate, dihydroartemisinin, artemether) toward leukemia, multiple myeloma, and lymphoma cells comprises oxidative stress response, inhibition of proliferation, induction of various types of cell death as apoptosis, autophagy, ferroptosis, inhibition of angiogenesis, and signal transducers, as NF-κB, MYC, amongst others. Therefore, new pharmaceutically active compounds, dimers, trimers, and hybrid molecules, could enhance the existing therapeutic alternatives in combating hematologic malignancies. Owing to the high potency and good tolerance without side effects of ARS-type drugs, combination therapies with standard chemotherapies could be applied in the future after further clinical trials in hematological malignancies. 10.1007/s00280-020-04170-5
    Cancer combination therapies with artemisinin-type drugs. Efferth Thomas Biochemical pharmacology Artemisia annua L. is a Chinese medicinal plant, which is used throughout Asia and Africa as tea or press juice to treat malaria. The bioactivity of its chemical constituent, artemisinin is, however, much broader. We and others found that artemisinin and its derivatives also exert profound activity against tumor cells in vitro and in vivo. Should artemisinin-type drugs be applied routinely in clinical oncology in the future, then it should probably be as part of combination therapy regimens rather than as monotherapy. In the present review, I give a comprehensive overview on synergistic and additive effects of artemisinin-type drugs in combination with different types of cytotoxic agents and treatment modalities: (a) standard chemotherapeutic drugs, (b) radiotherapy and photodynamic therapy, (c) established drugs for other indications than cancer, (d) novel synthetic compounds, (e) natural products and natural product derivatives, (f) therapeutic antibodies and recombinant proteins, and (g) RNA interference. I also summarize the activity of artemisinin-type drugs towards multidrug-resistant cells and tumor cells with other drug resistance phenomena. As synergistic interactions may not only occur in tumor cells, toxic reactions in normal cells (hepatotoxicity, drug interactions) were also considered. This review summarizes the scientific literature of more than 20years until the end of 2016. 10.1016/j.bcp.2017.03.019
    Artemisinin and its derivatives in cancer therapy: status of progress, mechanism of action, and future perspectives. Bhaw-Luximon Archana,Jhurry Dhanjay Cancer chemotherapy and pharmacology Since the late 1990s, there has been rapid multiplication of data on the anti-cancer properties of artemisinins. This article reviews the status of progress of artemisinin and its derivatives as anti-cancer agents in clinical trials, case reports, and in vitro/in vivo studies. Particular attention is laid on the combinations of artemisinins and synthetic chemodrugs to enhance the latter's efficacy. An attempt is here made to rationalize the synergistic effects of a few common anti-cancer drugs of the anthracycline, taxane, anti-metabolite, and platinum-based drug families. The various pathways that mediate the action of artemisinins as reported over the past decade are here summarized highlighting also the biomarkers that could be used to better predict the efficacy of the sesquiterpenoids. Their main action seems to be directed toward stalling tumor cell proliferation through cell cycle arrest mediated by reactive oxygen species (ROS). The emergence of artemisinins' nano-based formulations in combination with chemodrugs to enhance drug bioavailability and targeting as well as immunotherapy is also reviewed. The enhanced efficacy of artemisinin dimers compared to the parent molecules and standard chemotherapy is analyzed. While these therapies hold promises, it may be premature to conclude on their efficacy in the absence of clinical studies. 10.1007/s00280-017-3251-7
    Arsenic Trioxide and Artemisinin Act Synergistically to Kill Tumor Cells . Zhao Xiaoyan,Yang Sen,Zhang Duoduo,Li Zhubo,Huang Chengzhi Anti-cancer agents in medicinal chemistry BACKGROUND:Arsenic trioxide (AsO), which has been shown to be effective in treating leukemia and other solid tumors, was strictly restricted in clinical application due to its severe toxicity. The present study was performed to explore whether the combination of AsO and artemisinin could produce a more powerful anticancer effect and reduce the toxicity of AsO. METHOD:MTT assay was performed to detect the cell viability of A549, Hela and HepG2 cells treated with AsO and artemisinin. Combination Index (CI) analysis was carried out to evaluate the synergistic effect of AsO and artemisinin. Wound healing assay was performed to evaluate the migration rate. Fluorescent microscopy measurements and flow cytometry were used to evaluate the apoptosis. RESULT:Reactive Oxygen Species (ROS) was detected with DCFH-DA. The cell proliferation assay indicated that artemisinin significantly enhanced the inhibitory effect of AsO in a dose and time-dependent manner (P<0.01). Combination Index (CI) analysis further demonstrated that combining artemisinin with AsO generated synergistic effects in A549 (CI=0.65±0.05), Hela (CI=0.68±0.07) and HepG2 (CI=0.47±0.01) cells. The combination of these two drugs also evidently reduced the cell migration rate. Artemisinin also enhanced the apoptosis, necrosis in AsO- treated A549 and Hela cells. Combination of AsO and artemisinin significantly induced more apoptosis (22.1%) than AsO (5.68%) or ART (5.93%) alone in Hela cells. In addition, ROS levels were increased obviously by combining artemisinin with AsO. CONCLUSION:The present study indicated that combining artemisinin with AsO would be a novel therapeutic strategy for cancer therapy. 10.2174/1871520618666180903102630
    Synthesis of novel ring-contracted artemisinin dimers with potent anticancer activities. Zhang Ning,Yu Zhimei,Yang Xiaohong,Hu Ping,He Yun European journal of medicinal chemistry Artemisinin is a potential anticancer agent with an interesting trioxane sesquiterpene structure. In order to improve the biological activity and metabolic stability of artemisinin, a series of novel ring-contracted artemisinin dimers were synthesized. These dimers were evaluated by MTT assay against six cancer cell lines. Most of the dimmers exhibited improved antiproliferative activities over artemisinin. Especially, compound 8b showed the most pronounced anti-cancer activity for PC12 cancer cells with an IC value of 1.56 μM. Thus, PC12 cancer cells were used to further investigate the mechanism of antiproliferation for this series of compounds. Compound 8b arrested cell cycle at G1 phase and induced cell apoptosis via up-regulation of Bad, Bax, caspase-3 and caspase-9 protein expressions while inhibiting the expression of Bcl-xL. The present studies are the first to synthesize the ring-contracted artemisinin as dimers and show that these dimers have potent anti-tumor activities against several cancer cell lines. 10.1016/j.ejmech.2018.03.010
    Artemisinin induces selective and potent anticancer effects in drug resistant breast cancer cells by inducing cellular apoptosis and autophagy and G2/M cell cycle arrest. Guan Xing,Guan Yan Journal of B.U.ON. : official journal of the Balkan Union of Oncology PURPOSE:To investigate the anticancer properties of a well-known naturally occurring sesquiterpene lactone - artemisinin - against cisplatin resistant human breast carcinoma cells along with examining its effects on apoptosis, autophagy as well as cell cycle phase distribution. METHODS:MTT assay was used to study cytotoxic effects of artemisinin while clonogenic assay analysed its effects on cancer cell colony formation. Fluorescence microscopy using DAPI staining was employed to study apoptotic effects of artemisinin which was followed by annexin V/propidium iodide (PI) assay which quantified the apoptotic effects of artemisinin in cancer cells. Apoptotic effects of artemisinin were finally confirmed by western blot assay by analysing its effects on Bcl-2 and Bax protein expressions. Effects of artemisinin on autophagy were determined by transmission electron microscopy (TEM). Effects on cell cycle were analysed by flow cytometry and western blot. RESULTS:The results indicated that artemisinin led to considerable and dose-dependent antiproliferative effects on MDA-MB-231 cisplatin-resistant breast cancer cells with less toxicity in normal cell line, thus exhibiting selectivity. The colony formation decreased significantly as artemisinin dose increased. DAPI and comet assays revealed that artemisinin induced powerful apoptotic effects, triggering significant dose-dependent DNA damage. TEM indicated that artemisinin induced autophagy in MDA-MB-231 cisplatin-resistant human breast cancer cells by creating autophagosomes and autophagic vacuoles. The molecule also targeted G2/M phase cell cycle along with targeting some key cell cycle related proteins including cyclin-B1, cyclin D1 and cyclin E. CONCLUSION:The results show that artemisinin showed strong anticancer effects in MDA-MB-231 cisplatin-resistant cancer cells by triggering apoptosis and autophagy and G2/M phase arrest.
    Artemisinin and its derivatives prevent Helicobacter pylori-induced gastric carcinogenesis via inhibition of NF-κB signaling. Su Tao,Li Fangyuan,Guan Jiaji,Liu Linxin,Huang Ping,Wang Ying,Qi Xiaoxiao,Liu Zhongqiu,Lu Linlin,Wang Dawei Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:Gastric cancer has a high morbidity and is a leading cause of cancer-related mortality worldwide. Helicobacter pylori (H. pylori) infection is commonly found in the early stage of gastric cancer pathogenesis, which induces chronic gastritis. Artemisinin (ART) and its derivatives (ARTS, artesunate and DHA, dihydroartemisinin), a new class of potent antimalarials, have been reported to exert both preventive and anti-gastric cancer effects. However, the underlying mechanisms of the chemopreventive effects of ART and its derivatives in H. pylori infection induced-gastric cancer are not fully elucidated. PURPOSE:We investigated the effects of H. pylori infection in gastric cancer; and the preventive mechanisms of ART, ARTS and DHA. METHODS:The H. pylori growth was determined by the broth macro-dilution method, and its adhesion to gastric cancer cells was evaluated by using the urease assay. The protein and mRNA levels, reactive oxygen species (ROS) production, as well as the production of inflammatory cytokines were evaluated by Western blot, real-time PCR, flow cytometry and ELISA, respectively. Moreover, an in vivo MNU (N-methyl-N-nitroso-urea) and H. pylori-induced gastric adenocarcinoma mouse model was established for the investigation of the cancer preventive effects of ART and its derivaties, and the underlying mechanisms of action. RESULTS:ART, DHA and ARTS inhibited the growth of H. pylori and gastric cancer cells,suppressed H. pylori adhesion to the gastric cancer cells, and reduced the H. pylori-enhanced ROS production. Moreover, ART, DHA and ARTS significantly reduced tumor incidence, number of tumor nodules and tumor size in the mouse model. Among these three compounds, DHA exerted the most potent chemopreventive effect. Mechanistic studies showed that ART and its derivatives potently inhibited the NF-κB activation. CONCLUSION:ART, DHA and ARTS have potent preventive effects in H. pylori-induced gastric carcinogenesis. These effects are, at least in part, attributed to the inhibition of NF-κB signaling pathway. Our findings provide a molecular justification of using ART and its derivatives for the prevention and treatment of gastric cancer. 10.1016/j.phymed.2019.152968
    Artemisinin and Derivatives-Based Hybrid Compounds: Promising Therapeutics for the Treatment of Cancer and Malaria. Peter Sijongesonke,Jama Siphesihle,Alven Sibusiso,Aderibigbe Blessing A Molecules (Basel, Switzerland) Cancer and malaria are major health conditions around the world despite many strategies and therapeutics available for their treatment. The most used strategy for the treatment of these diseases is the administration of therapeutic drugs, which suffer from several shortcomings. Some of the pharmacological limitations associated with these drugs are multi-drug resistance, drug toxicity, poor biocompatibility and bioavailability, and poor water solubility. The currently ongoing preclinical studies have demonstrated that combination therapy is a potent approach that can overcome some of the aforementioned limitations. Artemisinin and its derivatives have been reported to exhibit potent efficacy as anticancer and antimalarial agents. This review reports hybrid compounds containing artemisinin scaffolds and their derivatives with promising therapeutic effects for the treatment of cancer and malaria. 10.3390/molecules26247521
    Artemisinin loaded chitosan magnetic nanoparticles for the efficient targeting to the breast cancer. Natesan Subramanian,Ponnusamy Chandrasekar,Sugumaran Abimanyu,Chelladurai Senthilkumar,Shanmugam Palaniappan Sharavanan,Palanichamy Rajaguru International journal of biological macromolecules Artemisinin, a natural anti-malarial agent, also possesses anti-proliferative and anti-angiogenic activity in cancer cells with very low toxicity to normal healthy cells. Drug loaded magnetic nanoparticles by using external magnetic field could selectively accumulate the drug at the target site and thereby reduce the doses required to achieve therapeutic concentration which may otherwise produce serious side effects on healthy cells. In the present study the artemisinin magnetic nanoparticles were successfully formulated using chitosan by ionic-gelation method. The developed magnetic nanoparticles of artemisinin were smooth and spherical in nature and their size was in the range of 349-445nm. The polydispersity index (PDI) and zeta potential of the formulated nanoparticles were in the range of 0.373-0.908 and -9.34 to -33.3 respectively. They showed 55% to 62.5% of drug encapsulation efficiency and 20% to 25% drug loading capacity. Around 62% to 78% of artemisinin was released from the artemisinin magnetic nanoparticles over the period of 48h. On application of physiologically acceptable external magnetic field, FITC conjugated artemisinin magnetic nanoparticles showed an enhanced accumulation of nanoparticles in the 4T1 breast tumour tissues of BALB/c mice model. 10.1016/j.ijbiomac.2017.03.137
    Inhibition of AKT enhances the anti-cancer effects of Artemisinin in clear cell renal cell carcinoma. Yu Congcong,Sun Peiyu,Zhou Yuehong,Shen Bin,Zhou Meihua,Wu Lingzhi,Kong Min Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Given studies have shown that Artemisinin (ART) reduces cancer cell proliferation, migration, invasion, tumorigenesis and metastasis. In this study, we evaluated the roles of ART in clear cell renal cell carcinoma (ccRCC) progression. We measured the eff ;ects of ART on cancer cell proliferation, colony formation, migration, invasion and tumorigenesis. CCK-8 assay demonstrated that ART inhibited cell growth with IC50 values 31.30 ± 0.73 μM in UMRC-2 and 23.97 ± 0.92 μM in CAKI-2, respectively. Colony formation assay shown that ART inhibited cell colony formation. Transwell migration and invasion assay shown that ART inhibited RCC migration and invasion. Realtime-qPCR assay shown that ART decreased the mRNA levels of proliferation related genes c-Myc, cyclin D1 and PCNA, and reduced the mRNA levels of mesenchymal genes N-cadherin, Vimentin and Snail, but increased the mRNA levels of epithelial marker E-cadherin. Moreover, ART inhibited AKT signaling pathway. In the presence of AKT inhibitor VIII, a pan-AKT inhibitor, ART reduced more cell proliferation, migration and invasion than in the absence of AKT inhibitor VIII, suggesting combination of ART and AKT inhibitor enhanced the anti-cancer effects of ART. Furthermore, the in vivo xenograft tumor model results suggested that ART decreased tumor size and weight, and suppressed AKT signaling. Taken together, our results indicated that ART inhibited ccRCC cell proliferation, colony formation, migration, invasion and tumorigenesis. Combination of ART and AKT inhibitor enhanced the anti-cancer cell proliferation, migration and invasion. 10.1016/j.biopha.2019.109383
    Artemisinin compounds sensitize cancer cells to ferroptosis by regulating iron homeostasis. Cell death and differentiation The antimalarial drug artemisinin and its derivatives have been explored as potential anticancer agents, but their underlying mechanisms are controversial. In this study, we found that artemisinin compounds can sensitize cancer cells to ferroptosis, a new form of programmed cell death driven by iron-dependent lipid peroxidation. Mechanistically, dihydroartemisinin (DAT) can induce lysosomal degradation of ferritin in an autophagy-independent manner, increasing the cellular free iron level and causing cells to become more sensitive to ferroptosis. Further, by associating with cellular free iron and thus stimulating the binding of iron-regulatory proteins (IRPs) with mRNA molecules containing iron-responsive element (IRE) sequences, DAT impinges on IRP/IRE-controlled iron homeostasis to further increase cellular free iron. Importantly, in both in vitro and a mouse xenograft model in which ferroptosis was triggered in cancer cells by the inducible knockout of GPX4, we found that DAT can augment GPX4 inhibition-induced ferroptosis in a cohort of cancer cells that are otherwise highly resistant to ferroptosis. Collectively, artemisinin compounds can sensitize cells to ferroptosis by regulating cellular iron homeostasis. Our findings can be exploited clinically to enhance the effect of future ferroptosis-inducing cancer therapies. 10.1038/s41418-019-0352-3
    Artemisinins as a novel anti-cancer therapy: Targeting a global cancer pandemic through drug repurposing. Augustin Yolanda,Staines Henry M,Krishna Sanjeev Pharmacology & therapeutics Artemisinins are a unique class of antimalarial drugs with significant potential for drug repurposing for a wide range of diseases including cancer. Cancer is a leading cause of death globally and the majority of cancer related deaths occur in Low and Middle Income Countries (LMICs) where conventional treatment options are often limited by financial cost. Drug repurposing can significantly shorten new therapeutic discovery pathways, ensuring greater accessibility and affordability globally. Artemisinins have an excellent safety and tolerability profile as well as being affordable for deployment in Low and Middle Class Income Countries at around USD1 per daily dose. Robust, well designed clinical trials of artemisinin drug repurposing are indicated for a variety of different cancers and treatment settings. 10.1016/j.pharmthera.2020.107706
    Artemisinin inhibits NRas palmitoylation by targeting the protein acyltransferase ZDHHC6. Cell chemical biology Protein S-palmitoylation is a post-translational modification that plays a crucial role in cancer cells by regulating the function and localization of oncoproteins and tumor suppressor proteins. Here, we identify artemisinin (ART), a clinically approved antimalarial endoperoxide natural product with promising anticancer activities, as an inhibitor of the ER-residing palmitoyl transferase ZDHHC6 in cancer cells using a chemoproteomic approach. We show that ART covalently binds and inhibits ZDHHC6 to reduce palmitoylation of the oncogenic protein NRas, disrupt NRas subcellular localization, and attenuate the downstream pro-proliferative signaling cascades. Our study identifies artemisinin as a non-lipid-based palmitoylation inhibitor targeting a specific palmitoyl acyltransferase and provides valuable mechanistic insights into the anticancer activity of artemisinins that are currently being studied in human clinical trials for different cancers. 10.1016/j.chembiol.2021.07.012
    Cell death mechanisms induced by synergistic effects of halofuginone and artemisinin in colorectal cancer cells. Gong Rui-Hong,Yang Da-Jian,Kwan Hiu-Yee,Lyu Ai-Ping,Chen Guo-Qing,Bian Zhao-Xiang International journal of medical sciences Our previous study found that the combination of halofuginone (HF) and artemisinin (ATS) synergistically arrest colorectal cancer (CRC) cells at the G1/G0 phase of the cell cycle; however, it remains unclear whether HF-ATS induces cell death. Here we report that HF-ATS synergistically induced caspase-dependent apoptosis in CRC cells. Specifically, both and experiments showed that HF or HF-ATS induces apoptosis via activation of caspase-9 and caspase-8 while only caspase-9 is involved in ATS-induced apoptosis. Furthermore, we found HF or HF-ATS induces autophagy; ATS can't induce autophagy until caspase-9 is blocked. Further analyzing the crosstalk between autophagic and caspase activation in CRC cells, we found autophagy is essential for activation of caspase-8, and ATS switches to activate capase-8 via induction of autophagy when caspase-9 is inhibited. When apoptosis is totally blocked, HF-ATS switches to induce autophagic cell death. This scenario was then confirmed in studies of chemoresistance CRC cells with defective apoptosis. Our results indicate that HF-ATS induces cell death via interaction between apoptosis and autophagy in CRC cells. These results highlight the value of continued investigation into the potential use of this combination in cancer therapy. 10.7150/ijms.66737
    The potential of artemisinins as anti-obesity agents via modulating the immune system. Shen Shengnan,Liao Qiwen,Lyu Ming,Wong Yin-Kwan,Zhang Xing,Zhou Jing,Ma Nan,Wang Jigang Pharmacology & therapeutics Artemisinin and its derivatives are the most effective antimalarial drugs. Besides anti-malarial activity, artemisinin and its derivatives have displayed wide-spectrum bioactivities such as anti-parasite, anti-tumor, and anti-obesity effects. Obesity is an epidemic worldwide which is a big threat to human health, but there are only a few approved anti-obesity drugs in the world. Also, these drugs are efficient to limited patients partly because their safety and efficacy are questioned. Anti-inflammatory therapies may be valuable in obesity treatment since growing evidence shows chronic metabolic inflammation is implicated in metabolic disease pathogenesis. As artemisinin and its derivatives display effective anti-inflammatory and immunoregulatory properties with less toxicity, it provides an insight for novel drug development in obesity therapeutic strategies via immune-regulatory mechanisms. In this review, the potential of artemisinin and its derivatives to treat various metabolic diseases such as obesity and diabetes is discussed. 10.1016/j.pharmthera.2020.107696
    Transcriptome analysis of genes associated with breast cancer cell motility in response to Artemisinin treatment. Kumari Kanchan,Keshari Sunita,Sengupta Debomita,Sabat Surendra C,Mishra Sandip K BMC cancer BACKGROUND:Well-known anti-malarial drug artemisinin exhibits potent anti-cancerous activities. In-vivo and in-vitro studies showed its anti-tumor and immunomodulatory properties signifying it as a potent drug candidate for study. The studies of mechanisms of cell movement are relevant which can be understood by knowing the involvement of genes in an effect of a drug. Although cytotoxicity and anti-proliferative activity of artemisinin is evident, the genes participating in its anti-migratory and reduced invasive effect are not well studied. The present study reports the alteration in the expression of 84 genes involved in cell motility upon artemisinin treatment in MCF-7 breast cancer cells using pathway focused gene expression PCR array. In addition, the effect of artemisinin on epigenetic modifier HDACs is studied. METHODS:We checked the functional stimulus of artemisinin on cell viability, migration, invasion and apoptosis in breast cancerous cell lines. Using qRT-PCR and western blot, we validated the altered expression of relevant genes associated with proliferation, migration, invasion, apoptosis and mammary gland development. RESULTS:Artemisinin inhibited cell proliferation of estrogen receptor negative breast cancer cells with fewer efficacies in comparison to estrogen receptor positive ones. At the same time, cell viability and proliferation of normal breast epithelial MCF10A cells was un-affected. Artemisinin strongly inhibited cancer cell migration and invasion. Along with orphan nuclear receptors (ERRα, ERRβ and ERRγ), artemisinin altered the ERα/ERβ/PR/Her expression status of MCF-7 cells. The expression of genes involved in the signaling pathways associated with proliferation, migration, invasion and apoptosis was significantly altered which cooperatively resulted into reduced growth promoting activities of breast cancer cells. Interestingly, artemisinin exhibited inhibitory effect on histone deacetylases (HDACs). CONCLUSIONS:Upregulated expression of tumor suppressor genes along with reduced expression of oncogenes significantly associated with growth stimulating signaling pathways in response to artemisinin treatment suggests its efficacy as an effective drug in breast cancer treatment. 10.1186/s12885-017-3863-7
    Disruption of mitochondrial homeostasis with artemisinin unravels anti-angiogenesis effects via auto-paracrine mechanisms. Tsui Kuan-Hao,Wu Meng-Yu,Lin Li-Te,Wen Zhi-Hong,Li Yi-Han,Chu Pei-Yi,Li Chia-Jung Theranostics : Tumor angiogenesis promotes tumor development, progression, growth, and metastasis. Metronomic chemotherapy involves the frequent administration of low-dose chemotherapeutic agents to block angiogenic activity and reduce side effects. : MDA-MB-231 cells were treated with various concentrations of artemisinin (ART) and vinorelbine (NVB) and the cytotoxic effects of ART/NVB were determined using the CCK-8 assay. Mitochondrial reactive oxygen species (ROS) levels, mitochondrial membrane potential (∆Ψm) and mass were assessed using MitoSOX, TMRE and MitoTracker green staining. Western blot analysis was used to quantify the expression of autophagy-related proteins. Herein, by using bioinformatics analysis and experimental verification, we identified CREB as a master in MDA-MB-231 cells. : We found that artemisinin (ART), which exhibits anti-angiogenic and anti-cancer effects via mitochondrial regulation, synergized with vinorelbine (NVB) to inhibit MDA-MB-231 cell proliferation. ART and NVB cooperated to regulate mitochondrial biogenesis. CREB acted as a crucial regulator of PGC1α and VEGF, which played critical roles in NVB-dependent growth factor depletion. Moreover, CREB suppression significantly reversed mitochondrial dysfunction following ART/NVB co-treatment. In addition, combination treatment with ART and NVB significantly suppressed tumor growth in a nude mouse xenograft model, with downregulated CREB and PGC1α expression levels observed in tumor biopsies, in agreement with our and data. : These findings support the hypothesis that ART affects cancer and endothelial cells by targeting the auto-paracrine effects of VEGF to suppress mitochondrial biogenesis, angiogenesis, and migration between cancer cells and endothelial cells. 10.7150/thno.33353
    The Potential Mechanisms by which Artemisinin and Its Derivatives Induce Ferroptosis in the Treatment of Cancer. Hu Yingying,Guo Nan,Yang Ting,Yan Jianghong,Wang Wenjun,Li Xiang Oxidative medicine and cellular longevity Artemisinin (ART) is a bioactive molecule derived from the Chinese medicinal plant Artemisia annua (Asteraceae). ART and artemisinin derivatives (ARTs) have been effectively used for antimalaria treatment. The structure of ART is composed of a sesquiterpene lactone, including a peroxide internal bridge that is essential for its activity. In addition to their well-known antimalarial effects, ARTs have been shown recently to resist a wide range of tumors. The antineoplastic mechanisms of ART mainly include cell cycle inhibition, inhibition of tumor angiogenesis, DNA damage, and ferroptosis. In particular, ferroptosis is a novel nonapoptotic type of programmed cell death. However, the antitumor mechanisms of ARTs by regulating ferroptosis remain unclear. Through this review, we focus on the potential antitumor function of ARTs by acting on ferroptosis, including the regulation of iron metabolism, generation of reactive oxygen species (ROS), and activation of endoplasmic reticulum stress (ERS). This article systematically reviews the recent progress in ferroptosis research and provides a basis for ARTs as an anticancer drug in clinical practice. 10.1155/2022/1458143
    Interactions between artemisinin derivatives and P-glycoprotein. Wang Yulin,Li Yongjie,Shang Dong,Efferth Thomas Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:Artemisinin was isolated and identified in 1972, which was the starting point for a new era in antimalarial drug therapy. Furthermore, numerous studies have demonstrated that artemisinin and its derivatives exhibit considerable anticancer activity both in vitro, in vivo, and even in clinical Phase I/II trials. P-glycoprotein (P-gp) mediated multi-drug resistance (MDR) is one of the most serious causes of chemotherapy failure in cancer treatment. Interestingly, many artemisinin derivatives exhibit excellent ability to overcome P-gp mediated MDR and even show collateral sensitivity against MDR cancer cells. Furthermore, some artemisinin derivatives show P-gp-mediated MDR reversal activity. Therefore, the interaction between P-gp and artemisinin derivatives is important to develop novel combination treatment protocols with artemisinin derivatives and established anticancer drugs that are P-gp substrates. PURPOSE:This systematic review provides an updated overview on the interaction between artemisinin derivatives and P-gp and the effect of artemisinin derivatives on the P-gp expression level. RESULTS:Artemisinin derivatives exhibit multi-specific interactions with P-gp. The currently used artemisinin derivatives are not transported by P-gp. However, some of novel synthetized artemisinin derivatives exhibit P-gp substrate properties. Furthermore, many artemisinin derivatives act as P-gp inhibitors, which exhibit the potential to reverse MDR towards clinically used anticancer drugs. CONCLUSION:Therefore, studies on the interaction between artemisinin derivatives and P-gp provide important information for the development of novel anti-cancer artemisinin derivatives to reverse P-gp mediated MDR and for the design of rational artemisinin-based combination therapies against cancer. 10.1016/j.phymed.2019.152998
    Ferroptosis: A Novel Mechanism of Artemisinin and its Derivatives in Cancer Therapy. Zhu Shunqin,Yu Qin,Huo Chunsong,Li Yuanpeng,He Linshen,Ran Botian,Chen Ji,Li Yonghao,Liu Wanhong Current medicinal chemistry BACKGROUND:Artemisinin is a sesquiterpene lactone compound with a special peroxide bridge that is tightly linked to the cytotoxicity involved in fighting malaria and cancer. Artemisinin and its derivatives (ARTs) are considered to be potential anticancer drugs that promote cancer cell apoptosis, induce cell cycle arrest and autophagy, inhibit cancer cell invasion and migration. Additionally, ARTs significantly increase intracellular Reactive Oxygen Species (ROS) in cancer cells, which result in ferroptosis, a new form of cell death, depending on the ferritin concentration. Ferroptosis is regarded as a cancer suppressor and as well as considered a new mechanism for cancer therapy. METHODS:The anticancer activities of ARTs and reference molecules were compared by literature search and analysis. The latest research progress on ferroptosis was described, with a special focus on the molecular mechanism of artemisinin-induced ferroptosis. RESULTS:Artemisinin derivatives, artemisinin-derived dimers, hybrids and artemisinin-transferrin conjugates, could significantly improve anticancer activity, and their IC50 values are lower than those of reference molecules such as doxorubicin and paclitaxel. The biological activities of linkers in dimers and hybrids are important in the drug design processes. ARTs induce ferroptosis mainly by triggering intracellular ROS production, promoting the lysosomal degradation of ferritin and regulating the System Xc-/Gpx4 axis. Interestingly, ARTs also stimulate the feedback inhibition pathway. CONCLUSION:Artemisinin and its derivatives could be used in the future as cancer therapies with broader applications due to their induction of ferroptosis. Meanwhile, more attention should be paid to the development of novel artemisinin-related drugs based on the mechanism of artemisinininduced ferroptosis. 10.2174/0929867327666200121124404
    Combination Therapies of Artemisinin and its Derivatives as a Viable Approach for Future Cancer Treatment. Kumar Maushmi S,Yadav Tanuja T,Khair Rohan R,Peters Godefridus J,Yergeri Mayur C Current pharmaceutical design BACKGROUND:Many anticancer drugs have been developed for clinical usage till now, but the major problem is the development of drug-resistance over a period of time in the treatment of cancer. Anticancer drugs produce huge adverse effects, ultimately leading to death of the patient. Researchers have been focusing on the development of novel molecules with higher efficacy and lower toxicity; the anti-malarial drug artemisinin and its derivatives have exhibited cytotoxic effects. METHODS:We have done extensive literature search for artemisinin for its new role as anti-cancer agent for future treatment. Last two decades papers were referred for deep understanding to strengthen its role. RESULT:Literature shows changes at 9, 10 position in the artemisinin structure produces anticancer activity. Artemisinin shows anticancer activity in leukemia, hepatocellular carcinoma, colorectal and breast cancer cell lines. Artemisinin and its derivatives have been studied as combination therapy with several synthetic compounds, RNA interfaces, recombinant proteins and antibodies etc., for synergizing the effect of these drugs. They produce an anticancer effect by causing cell cycle arrest, regulating signaling in apoptosis, angiogenesis and cytotoxicity activity on the steroid receptors. Many novel formulations of artemisinin are being developed in the form of carbon nanotubes, polymer-coated drug particles, etc., for delivering artemisinin, since it has poor water/ oil solubility and is chemically unstable. CONCLUSION:We have summarize the combination therapies of artemisinin and its derivatives with other anticancer drugs and also focussed on recent developments of different drug delivery systems in the last 10 years. Various reports and clinical trials of artemisinin type drugs indicated selective cytotoxicity along with minimal toxicity thus projecting them as promising anti-cancer agents in future cancer therapies. 10.2174/1381612825666190902155957
    Artemisinin Inhibits the Migration and Invasion in Uveal Melanoma via Inhibition of the PI3K/AKT/mTOR Signaling Pathway. Farhan Mohd,Silva Marta,Xingan Xing,Zhou Zhiwei,Zheng Wenhua Oxidative medicine and cellular longevity Uveal melanoma is the most common primary ocular neoplasm in adults, with many patients ending up developing liver metastasis and facing a significant reduction of their life expectancy due to the lack of efficient treatments. Artemisinin is an antimalarial drug that has been widely used in the clinic and whose anticancer properties have also been described. Its reported safety, affordability, and ability to reach the ocular tissues point that it has a potential therapeutic agent against uveal melanoma. In the present study, we found that a subantimalaria dosage of artemisinin significantly attenuated the migration and invasion potential of uveal melanoma cells, in a concentration-dependent manner. Assessment of the mechanisms underlying artemisinin anticancer action revealed that its use dramatically reduced the phosphorylation of PI3K, AKT, and mTOR in UM cells. Further inhibition of PI3K signaling, using LY294002, or of mTOR, by rapamycin, blocked the migration and invasion of UM cells similarly to artemisinin. In contrast, AKT or mTOR activator (Sc79 and MHY1485, respectively) attenuated the inhibitory effect of artemisinin on the migration and invasion abilities of UM cells, further validating that artemisinin's anticancer effect is likely to be mediated via inhibition of the PI3K/AKT/mTOR pathway. Artemisinin also induced mitochondrial membrane potential loss and apoptosis of UM cells, having no significant toxic effect on normal retinal neuronal cells RGC-5 and epithelial cells D407. These findings and the reported safety of artemisinin's clinical dosage strongly suggest the therapeutic potential of artemisinin in the prevention and treatment of uveal melanomas. 10.1155/2021/9911537
    Artemisinin-derived hybrids and their anticancer activity. Gao Feng,Sun Zhou,Kong Fangong,Xiao Jiaqi European journal of medicinal chemistry The emergence of drug-resistance and the low specificity of anticancer agents are the major challenges in the treatment of cancer and can result in many side effects, creating an urgent demand to develop novel anticancer agents. Artemisinin-derived compounds, bearing a peroxide-containing sesquiterpene lactone moiety, could form free radicals with high reactivity and possess diverse pharmaceutical properties including in vitro and in vivo anticancer activity besides their typical antimalarial activity. Hybrid molecules have the potential to improve the specificity and overcome the drug resistance, therefore hybridization of artemisinin skeleton with other anticancer pharmacophores may provide novel anticancer candidates with high specificity and great potency against drug-resistant cancers. The review outlines the recent advances of artemisinin-derived hybrids as potential anticancer agents, and the structure-activity relationships are also discussed to provide an insight for rational designs of novel hybrids with high activity. 10.1016/j.ejmech.2020.112044
    Novel artemisinin derivatives with potent anticancer activities and the anti-colorectal cancer effect by the mitochondria-mediated pathway. Lin Lan,Lu Wenyu,Dai Tianzhi,Chen Huan,Wang Tong,Yang Li,Yang Xuelian,Liu Ying,Sun Dequn Bioorganic chemistry Many artemisinin derivatives have good inhibitory effects on malignant tumors. In this work, a novel series of artemisinin derivatives containing piperazine and fluorine groups were designed and synthesized and their structures were confirmed by H NMR, C NMR and HRMS technologies. The in vitro cytotoxicity against various cancer cell lines was evaluated. Among the derivatives, compound 12h was found to exhibit not only the best activity against HCT-116 cells (IC = 0.12 ± 0.05 μM), but also low toxicity against normal cell line L02 (IC = 12.46 ± 0.10 μM). The mechanisms study revealed that compound 12h caused the cell cycle arrest in G1 phase, induced apoptosis in a concentration-dependent manner, significantly reduced mitochondrial membrane potential, increased intracellular ROS and Ca levels, up-regulated the expression of Bax, cleaved caspase-9, cleaved caspase-3, and down-regulated the expression of Bcl-2 protein. A series of analyses confirmed that 12h can inhibit HCT-116 cells migration and induce apoptosis by a mechanism of the mitochondria-mediated pathway in the HCT-116 cell line. The present work indicates that compound 12h may merit further investigation as a potential therapeutic agent for colorectal cancer. 10.1016/j.bioorg.2020.104496
    Targeting autophagy enhances the anticancer effect of artemisinin and its derivatives. Sun Xin,Yan Peiyi,Zou Chang,Wong Yin-Kwan,Shu Yuhan,Lee Yew Mun,Zhang Chongjing,Yang Nai-Di,Wang Jigang,Zhang Jianbin Medicinal research reviews Artemisinin and its derivatives, with their outstanding clinical efficacy and safety, represent the most effective and impactful antimalarial drugs. Apart from its antimalarial effect, artemisinin has also been shown to exhibit selective anticancer properties against multiple cancer types both in vitro and in vivo. Specifically, our previous studies highlighted the therapeutic effects of artemisinin on autophagy regulation. Autophagy is a well-conserved degradative process that recycles cytoplasmic contents and organelles in lysosomes to maintain cellular homeostasis. The deregulation of autophagy is often observed in cancer cells, where it contributes to tumor adaptation to nutrient-deficient tumor microenvironments. This review discusses recent advances in the anticancer properties of artemisinin and its derivatives via their regulation of autophagy, mitophagy, and ferritinophagy. In particular, we will discuss the mechanisms of artemisinin activation in cancer and novel findings regarding the role of artemisinin in regulating autophagy, which involves changes in multiple signaling pathways. More importantly, with increasing failure rates and the high cost of the development of novel anticancer drugs, the strategy of repurposing traditional therapeutic Chinese medicinal agents such as artemisinin to treat cancer provides a more attractive alternative. We believe that the topics covered here will be important in demonstrating the potential of artemisinin and its derivatives as safe and potent anticancer agents. 10.1002/med.21580
    Artemisinin enhances the anti-tumor immune response in 4T1 breast cancer cells in vitro and in vivo. Cao Yu,Feng Yong-Hui,Gao Li-Wei,Li Xiao-Ying,Jin Quan-Xiu,Wang Yu-Ying,Xu Ying-Ying,Jin Feng,Lu Shi-Long,Wei Min-Jie International immunopharmacology BACKGROUND:Breast cancer is a prominent cause of death among women worldwide. Recent studies have demonstrated that artemisinin (ART) displays anti-tumor activity. Using a mouse breast cancer model, we investigated the effects of ART in vitro and in vivo to determine how it influences the anti-tumor immune response. METHODS:We measured the proliferation and apoptosis of 4T1 cells in vitro after ART treatment by MTT assay and FACS. To examine the effects of ART in vivo, tumor volumes and survival rates were measured in 4T1 tumor-bearing mice. FACS was used to determine the frequencies of Tregs, MDSCs, CD4 IFN-γ T cells, and CTLs in the tumors and spleens of the mice. mRNA levels of the transcription factors T-bet and FOXP3 and cytokines IFN-γ, TNF-α, TGF-β, and IL-10 were also determined by real-time RT-PCR. ELISA was used to measure TGF-β protein levels in the cell culture supernatants. RESULTS:ART supplementation significantly increased 4T1 cell apoptosis and decreased TGF-β levels in vitro. ART also impeded tumor growth in 4T1 TB mice and extended their survival. MDSC and Treg frequencies significantly decreased in the 4T1 TB mice after ART treatment while CD4 IFN-γ T cells and CTLs significantly increased. ART significantly increased T-bet, IFN-γ, and TNF-α mRNA levels within the tumor and significantly decreased TGF-β mRNA levels. CONCLUSION:ART supplementation hindered 4T1 tumor growth in vivo by promoting T cell activation and quelling immunosuppression from Tregs and MDSCs in the tumor. 10.1016/j.intimp.2019.01.041
    Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action. Wong Yin Kwan,Xu Chengchao,Kalesh Karunakaran A,He Yingke,Lin Qingsong,Wong W S Fred,Shen Han-Ming,Wang Jigang Medicinal research reviews Artemisinin and its derivatives (collectively termed as artemisinins) are among the most important and effective antimalarial drugs, with proven safety and efficacy in clinical use. Beyond their antimalarial effects, artemisinins have also been shown to possess selective anticancer properties, demonstrating cytotoxic effects against a wide range of cancer types both in vitro and in vivo. These effects appear to be mediated by artemisinin-induced changes in multiple signaling pathways, interfering simultaneously with multiple hallmarks of cancer. Great strides have been taken to characterize these pathways and to reveal their anticancer mechanisms of action of artemisinin. Moreover, encouraging data have also been obtained from a limited number of clinical trials to support their anticancer property. However, there are several key gaps in knowledge that continue to serve as significant barriers to the repurposing of artemisinins as effective anticancer agents. This review focuses on important and emerging aspects of this field, highlighting breakthroughs in unresolved questions as well as novel techniques and approaches that have been taken in recent studies. We discuss the mechanism of artemisinin activation in cancer, novel and significant findings with regards to artemisinin target proteins and pathways, new understandings in artemisinin-induced cell death mechanisms, as well as the practical issues of repurposing artemisinin. We believe these will be important topics in realizing the potential of artemisinin and its derivatives as safe and potent anticancer agents. 10.1002/med.21446
    Structural optimization and biological evaluation for novel artemisinin derivatives against liver and ovarian cancers. Zhou Yu,Li Xiaoguang,Chen Kerong,Ba Qian,Zhang Xu,Li Jingquan,Wang Jinfang,Wang Hui,Liu Hong European journal of medicinal chemistry An increasing number of artemisinin (ARS) and its derivatives have been reported for their potential therapeutic value of human cancer. However, their therapeutic potencies are limited owing to their poor pharmacokinetic profiles. Our previous studies showed that a lead compound ARS4 originated from incorporating the pharmacophore of the approved chemotherapeutic agent melphalan into the basic skeleton of artemisinin with a succinic linker exhibited an excellent toxicity to human ovarian cancer cells and low cytotoxicity to normal cells. The mechanism studies demonstrated that it inhibited the growth and proliferation of ovarian cancer cells and resulted in S-phase arrest, apoptosis and inhibition of migration. Meanwhile, it exhibited excellent antitumor activities in animal models. Herein, further structure optimization for this lead compound ARS4 was performed and nineteen novel derivatives were designed and synthesized. Among them, compounds 10-12, 15, 16, 18 and 19 demonstrated powerful cytotoxic effects against human liver cancer and ovarian cancer cell lines, with their IC below 0.86 μM against Hep3B and A2780 cell lines, which are superior to that of ARS4. Four compounds (11, 15, 16 and 18) were selected to further evaluate their antitumor activities in in vitro and in vivo ovarian and liver cancer models, the results indicated that compound 18 exhibited the best therapeutic effect, not only effectively inhibited the growth of 7404 xenograft and Huh7 xenograft, but also presented a good dose-dependent inhibition toward the growth of A2780 xenograft. Overall, based on these positive results, these novel chemical structures may provide a new inspiration for the discovery of novel antitumor agents originated from artemisinin scaffolds. 10.1016/j.ejmech.2020.113000
    Antitumor and anti-angiogenic effects of artemisinin on breast tumor xenografts in nude mice. Dong Jing,Chen Yuelei,Yang Wenhui,Zhang Xi,Li Lin Research in veterinary science Breast cancer is a high incidence disease in humans. Artemisinin is an important extract that is widely used as an antimalarial drug which also serve as effective treatments for cancer. 32 nude mice were injected with 0.2 ml of MDA-MB-231 cell suspension of 2 × 10 cells/ml respectively. The nude mice models were randomly divided into four groups of 8 in each group. Each group was given daily gavage, high dose group: 200 mg/kg/0.1 ml, middle dose group 100 mg/kg/0.1 ml, low dose group 50 mg/kg/0.1 ml, control group: 0.1 ml vegetable oil was fed continuously for 21 days. ELISA was used to detect serum vascular endothelial growth the content of factor VEGF and hypoxia-inducible factor HIF-1α were detected. The expression of Notch pathway-related factors in tumor tissue was detected by fluorescence quantitative assay. ELISA results showed that the serum VEGF decreased significantly in the high dose group compared with the control group (p < .01), while the other dose groups did not have significant (p > .05). The serum HIF-1α in the high dose group compared with the control group, the decrease in HIF-1α was significant (p < .05), and the other groups were not significant (p > .05). The result of fluorescence quantitative section showed that artemisinin could down-regulate the expression of notch signaling related factors notch1, Dll4 and Jagged1, and 200 mg/kg dose group had the most significant effect. It may inhibit the development of tumors by reducing serum angiogenesis-related factors VEGF, HIF-1ɑ and inhibiting the activity of notch1 signaling pathway related factors. 10.1016/j.rvsc.2020.01.005
    Inactivation of PDH can Reduce Anaplastic Thyroid Cancer Cells' Sensitivity to Artemisinin. Anti-cancer agents in medicinal chemistry BACKGROUND:Anaplastic Thyroid Cancer (ATC) is a rare subtype of thyroid tumors with a high mortality rate. Targeted therapies against ATC are ineffective and mostly transient. Artemisinin has shown excellent anti-tumor activity in several cancers, but its effects on ATC are still unknown. OBJECTIVE:To evaluate the effects of artemisinin on ATC cells and assess the mechanism underlying drug resistance. METHODS:The viability and proliferation rates of the artemisinin-treated CAL-62 and BHT-101 cells were analyzed by MTT and EdU incorporation assays. The protein expression levels were determined by Tandem Mass Tag (TMT) labeling quantitative proteomics and western blotting. RESULTS:Artemisinin treatment significantly decreased the expression levels of COX2 and COX7A2 and increased that of COX14, YEM1l1, ALAS1, and OAT after 48h. In addition, FTL was upregulated in the CAL-62 cells and downregulated in BHT-101 cells. The CAL-62 cells showed transient and reversible resistance to artemisinin, which was correlated to time-dependent changes in HIF1α, PDK1, and PDHA levels. CONCLUSION:Artemisinin targets the mitochondrial respiratory chain proteins in ATC cells. CAL-62 cells show transient resistance to artemisinin via PDH downregulation, indicating that PDH activation may enhance the cytotoxic effects of artemisinin on ATC cells. 10.2174/1871520621666210910100803
    The current scenario on anticancer activity of artemisinin metal complexes, hybrids, and dimers. Archiv der Pharmazie Cancer, the most significant cause of morbidity and mortality, has already posed a heavy burden on health care systems globally. In recent years, cancer treatment has made a significant breakthrough, but cancer cells inevitably acquire resistance, and the efficacy of the treatment is greatly reduced as the tumor progresses. To overcome the above issues, novel chemotherapeutics are needed urgently. Artemisinin and its derivatives-sesquiterpene lactone compounds possessing a unique peroxy bridge moiety-exhibit excellent safety and tolerability profiles. Mechanistically, artemisinin derivatives can promote cancer cell apoptosis, induce cell cycle arrest and autophagy, and inhibit cancer cell invasion and migration. Accordingly, artemisinin derivatives demonstrate promising anticancer efficacy both in vitro and in vivo, and even in clinical Phase I/II trials. The purpose of the present review article is to provide an emphasis on the current scenario (January 2017-January 2022) of artemisinin derivatives with potential anticancer activity, inclusive of artemisinin metal complexes, hybrids, and dimers. The structure-activity relationships and mechanisms of action are also discussed to facilitate the further rational design of more effective candidates. 10.1002/ardp.202200086
    Artemisinin-derived dimers as potential anticancer agents: Current developments, action mechanisms, and structure-activity relationships. Zhang Bo Archiv der Pharmazie Anticancer agents play a pivotal role in cancer treatment. However, most of the anticancer drugs currently used in the clinics have a severe anticancer scenario, as well as low specificity and fatal side effects. Thus, there is an urgent demand to develop novel drugs with great efficacy, high specificity, and low side effects. Artemisinin and its semisynthetic derivatives are mainstays of chemotherapy against malaria, and artemisinin-based compounds, especially artemisinin-derived dimers, also exhibit excellent in vitro and in vivo anticancer activity. The structure-activity relationship (SAR) demonstrated that the linker between the two artemisinin moieties influenced the anticancer activity significantly; so, the rational design of the linker may provide valuable therapeutic intervention for the treatment of cancer. This review outlines the potential anticancer activity of artemisinin-derived dimers tethered by different linkers. The SARs, as well as mechanisms of action, are discussed to provide insights for the rational design of more effective dimers. 10.1002/ardp.201900240
    Discovery and repurposing of artemisinin. Frontiers of medicine Malaria is an ancient infectious disease that threatens millions of lives globally even today. The discovery of artemisinin, inspired by traditional Chinese medicine (TCM), has brought in a paradigm shift and been recognized as the "best hope for the treatment of malaria" by World Health Organization. With its high potency and low toxicity, the wide use of artemisinin effectively treats the otherwise drug-resistant parasites and helps many countries, including China, to eventually eradicate malaria. Here, we will first review the initial discovery of artemisinin, an extraordinary journey that was in stark contrast with many drugs in western medicine. We will then discuss how artemisinin and its derivatives could be repurposed to treat cancer, inflammation, immunoregulation-related diseases, and COVID-19. Finally, we will discuss the implications of the "artemisinin story" and how that can better guide the development of TCM today. We believe that artemisinin is just a starting point and TCM will play an even bigger role in healthcare in the 21st century. 10.1007/s11684-021-0898-6
    Antitumor activity of the combination of artemisinin and epirubicin in human leukemia cells. Folia medica AIM:We evaluated the tumor-inhibiting effect of artemisinin applied separately and in combination with epirubicin on leukemia HL-60 and HL-60/Dox cell lines, its dose modulation effect and its potency to  influence iron-induced oxidative damage of biologically relevant molecules. MATERIALS AND METHODS:MTT assay and the method of Chou-Talalay were used to show the inhibition of tumor cell proliferation and to evaluate the synergistic effect and modulation effect of artemisinin and epirubicin at varying concentrations. We also used spectrophotometric assays to determine the potency of artemisinin to influence iron-induced molecular degradation of lecithin and deoxyribose. RESULTS:Artemisinin exhibits tumor-inhibiting effect on both the anthracycline-sensitive and anthracycline-resistant promyelocytic cell lines, reaching 88% and 61% (T/C), respectively, when applied at higher concentrations in a dose-dependent manner. The combination of artemisinin and epirubicin shows synergistic effects in all tested concentrations on doxorubicin-resistant cells (CI<0.7). Artemisinin sensitizes the resistant cells towards epirubicin as shown by the CI (combination index) values and has a dose-modulation effect as shown by DRI (dose reduction index). Artemisinin induces deoxyribose oxidative degradation when applied alone and exerts synergistic deoxyribose degradation effect when applied with iron. However, artemisinin does not influence the studied processes in the lecithin-containing model system and has no potential to induce lipid peroxidation. CONCLUSIONS:This study presents a new opportunity to enhance the effectiveness of epirubicin-based treatment regimens with addition of artemisinins for resistant tumors. 10.3897/folmed.63.e55938
    Anti-malarial drug, artemisinin and its derivatives for the treatment of respiratory diseases. Cheong Dorothy H J,Tan Daniel W S,Wong Fred W S,Tran Thai Pharmacological research Artemisinins are sesquiterpene lactones with a peroxide moiety that are isolated from the herb Artemisia annua. It has been used for centuries for the treatment of fever and chills, and has been recently approved for the treatment of malaria due to its endoperoxidase properties. Progressively, research has found that artemisinins displayed multiple pharmacological actions against inflammation, viral infections, and cell and tumour proliferation, making it effective against diseases. Moreover, it has displayed a relatively safe toxicity profile. The use of artemisinins against different respiratory diseases has been investigated in lung cancer models and inflammatory-driven respiratory disorders. These studies revealed the ability of artemisinins in attenuating proliferation, inflammation, invasion, and metastasis, and in inducing apoptosis. Artemisinins can regulate the expression of pro-inflammatory cytokines, nuclear factor-kappa B (NF-κB), matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), promote cell cycle arrest, drive reactive oxygen species (ROS) production and induce Bak or Bax-dependent or independent apoptosis. In this review, we aim to provide a comprehensive update of the current knowledge of the effects of artemisinins in relation to respiratory diseases to identify gaps that need to be filled in the course of repurposing artemisinins for the treatment of respiratory diseases. In addition, we postulate whether artemisinins can also be repurposed for the treatment of COVID-19 given its anti-viral and anti-inflammatory properties. 10.1016/j.phrs.2020.104901
    Artemisinin potentiates apoptosis and triggers cell cycle arrest to attenuate malignant growth of salivary gland tumor cells. Xiao Peng,Liang Qiujuan,Chen Qiuqiu,Liu Haixia Acta biochimica Polonica One of the rare malignant tumors developing within the glands of the buccal cavity in human beings is salivary gland tumors (SGTs). The hallmark of SGTs is the fusion of nuclear factor IB (NFIB) and myeloblastosis (MYB) genes developed after the translocation of q22-23; p23-24. Although the aetiology of SGTs is not clear, however, the therapeutic modalities are surgical resection followed by the combination of chemotherapy and radiotherapy if a chance of recurrence seems to develop. Owing to have numerous side effects of chemotherapy, the drug development has been shifted to natural products with minimal side effects. One of the key phytochemical artemisinin derived from wormwood Artemisia annua exhibits various pharmacological activities against various in-vivo and in-vitro cellular models. Here, we evaluated the cytotoxic potential of artemisinin against A-253 cells with possible underlying cell death mechanisms. Our results showed that artemisinin reduces the proliferation of cells in a concentration-dependent manner and displays IC50 value in a range of 10.23, 14.21 μM, and 203.18 μM against A-253/HTB-41 and transformed salivary gland SMIE cells, respectively. Flow cytometry analysis demonstrated that artemisinin promotes a significant amount of apoptotic cellular population and triggers G0/G1 arrest of A-253 cells in a concentration-dependent manner. To verify the mechanism of cell death induced by artemisinin in A-253 cells, we found an increased level of Bax, Bim, Bad, Bak and reduced level of antiapoptotic protein Bcl-2, Bcl-XL with concomitant release of mitochondrial resident protein cytochrome c into the cytoplasm. Additionally, we found that artemisinin augments the production of reactive oxygen species which further leads to the activation of proapoptotic proteins PARP1, and caspase-3, in a concentration-dependent manner thereby triggering apoptosis. In conclusion, artemisinin exhibits promising anticancer therapeutic potential against A-253 cells and needs further validation of in-vitro results in preclinical models. 10.18388/abp.2020_5845
    Therapeutic Potentials and Mechanisms of Artemisinin and its Derivatives for Tumorigenesis and Metastasis. Li Yue,Zhou Xiaoyan,Liu Jiali,Yuan Xiaohong,He Qian Anti-cancer agents in medicinal chemistry BACKGROUND:Tumor recurrence and metastasis are still leading causes of cancer mortality worldwide. The influence of traditional treatment strategies against metastatic tumors may still be limited. To search for novel and powerful agents against tumors has become a major research focus. In this study, Artemisinin (ARM), a natural compound isolated from herbs, Artemisia annua L., proceeding from drug repurposing methods, attracts more attention due to its good efficacy and tolerance in antimalarial practices, as well as newly confirmed anticancer activity. METHODS:We have searched and reviewed the literatures about ARM and its derivatives (ARMs) for cancer using keywords "artemisinin" until May 2019. RESULTS:In preclinical studies, ARMs can induce cell cycle arrest and cell death by apoptosis etc., to inhibit the progression of tumors, and suppress EMT and angiogenesis to inhibit the metastasis of tumors. Notably, the complex relationships of ARMs and autophagy are worth exploring. Inspired by the limitations of its antimalarial applications and the mechanical studies of artemisinin and cancer, people are also committed to develop safer and more potent ARM-based modified compounds (ARMs) or combination therapy, such as artemisinin dimers/ trimers, artemisinin-derived hybrids. Some clinical trials support artemisinins as promising candidates for cancer therapy. CONCLUSION:ARMs show potent therapeutic potentials against carcinoma including metastatic tumors. Novel compounds derived from artemisinin and relevant combination therapies are supposed to be promising treatment strategies for tumors, as the important future research directions. 10.2174/1871520620666200120100252
    Mechanisms and Molecular Targets of Artemisinin in Cancer Treatment. Li Dongning,Zhang Jie,Zhao Xiaoyan Cancer investigation The major problems with cancer therapy are drug-induced side effects. There is an urgent need for safe anti-tumor drugs. Artemisinin is a Chinese herbal remedy for malaria with efficacy and safety. However, several studies reported that artemisinin causes neurotoxicity and cardiotoxicity in animal models. Recently, nanostructured drug delivery systems have been designed to improve therapeutic efficacy and reduce toxicity. Artemisinin has been reported to show anticancer properties. The anticancer effects of artemisinin appear to be mediated by inducing cell cycle arrest, promoting ferroptosis and autophagy, inhibiting cell metastasis. Therefore, the review is to concentrate on mechanisms and molecular targets of artemisinin as anti-tumor agents. We believe these will be important topics in realizing the potential of artemisinin and its derivatives as potent anticancer agents. 10.1080/07357907.2021.1954190
    Artemisinin and its derivatives: a promising cancer therapy. Kiani Bushra Hafeez,Kayani Waqas Khan,Khayam Asma Umer,Dilshad Erum,Ismail Hammad,Mirza Bushra Molecular biology reports The world is experiencing a cancer epidemic and an increase in the prevalence of the disease. Cancer remains a major killer, accounting for more than half a million deaths annually. There is a wide range of natural products that have the potential to treat this disease. One of these products is artemisinin; a natural product from Artemisia plant. The Nobel Prize for Medicine was awarded in 2015 for the discovery of artemisinin in recognition of the drug's efficacy. Artemisinin produces highly reactive free radicals by the breakdown of two oxygen atoms that kill cancerous cells. These cells sequester iron and accumulate as much as 1000 times in comparison with normal cells. Generally, chemotherapy is toxic to both cancerous cells and normal cells, while no significant cytotoxicity from artemisinin to normal cells has been found in more than 4000 case studies, which makes it far different than conventional chemotherapy. The pleiotropic response of artemisinin in cancer cells is responsible for growth inhibition by multiple ways including inhibition of angiogenesis, apoptosis, cell cycle arrest, disruption of cell migration, and modulation of nuclear receptor responsiveness. It is very encouraging that artemisinin and its derivatives are anticipated to be a novel class of broad-spectrum antitumor agents based on efficacy and safety. This review aims to highlight these achievements and propose potential strategies to develop artemisinin and its derivatives as a new class of cancer therapeutic agents. 10.1007/s11033-020-05669-z