Imaging of hydrogen peroxide (HO) during the ferroptosis process in living cancer cells with a practical fluorescence probe.
Hydrogen peroxide (HO) plays an important role in intracellular signal transduction pathway. It has been closely associated with the occurrence and development of tumors as well as the recent studied ferroptosis. In this work, monitoring the HO level during the ferroptosis process in living cancer cells was achieved by using a new practical fluorescence probe, HP, accompanying with a series of property evaluation and model construction. As a practical tool, HP indicated high sensitivity (LOD 0.77 μM), high selectivity and low toxicity. Most satisfactorily, it could realize the applications of mapping the variation of intracellular HO level regulated by the inducer or activator and visualizing the HO release event as a significant feature during the ferroptosis process. This work was a challenging trial to monitor dynamic parameters of ferroptosis, and offered crucial information about the role of HO for investigating further physiological or pathological processes.
Iron and thiol redox signaling in cancer: An exquisite balance to escape ferroptosis.
Toyokuni Shinya,Ito Fumiya,Yamashita Kyoko,Okazaki Yasumasa,Akatsuka Shinya
Free radical biology & medicine
Epidemiological data indicate a constant worldwide increase in cancer mortality, although the age of onset is increasing. Recent accumulation of genomic data on human cancer via next-generation sequencing confirmed that cancer is a disease of genome alteration. In many cancers, the Nrf2 transcription system is activated via mutations either in Nrf2 or Keap1 ubiquitin ligase, leading to persistent activation of the genes with antioxidative functions. Furthermore, deep sequencing of passenger mutations is clarifying responsible cancer causative agent(s) in each case, including aging, APOBEC activation, smoking and UV. Therefore, it is most likely that oxidative stress is the principal initiating factor in carcinogenesis, with the involvement of two essential molecules for life, iron and oxygen. There is evidence based on epidemiological and animal studies that excess iron is a major risk for carcinogenesis, suggesting the importance of ferroptosis-resistance. Microscopic visualization of catalytic Fe(II) has recently become available. Although catalytic Fe(II) is largely present in lysosomes, proliferating cells harbor catalytic Fe(II) also in the cytosol and mitochondria. Oxidative stress catalyzed by Fe(II) is counteracted by thiol systems at different functional levels. Nitric oxide, carbon monoxide and hydrogen (per)sulfide modulate these reactions. Mitochondria generate not only energy but also heme/iron sulfur cluster cofactors and remain mostly dysfunctional in cancer cells, leading to Warburg effects. Cancer cells are under persistent oxidative stress with a delicate balance between catalytic iron and thiols, thereby escaping ferroptosis. Thus, high-dose L-ascorbate and non-thermal plasma as well as glucose/glutamine deprivation may provide additional benefits as cancer therapies over preexisting therapeutics.
Real-Time Imaging Redox Status in Biothiols and Ferric Metabolism of Cancer Cells in Ferroptosis Based on Switched Fluorescence Response of Gold Carbon Dots.
Xie Xiaoxue,Hua Xinyi,Wang Ziqi,Yang Xiumei,Huang Haowen
Ferroptosis is an iron-dependent form of regulated cell death. In this study, a ratiometric fluorescent probe, gold carbon dots (GCDs) consisting of carbon skeleton and gold nanoclusters, was used for in situ imaging to monitor redox status in biothiols (glutathione and cysteine) and ferric metabolism of cancer cells in ferroptosis. The as-prepared GCDs can selectively respond to biothiols, interestingly, the fluorescence may be switched to sense ferric ions without interference by biothiols under proper conditions. The robust GCDs-probe exhibits excellent photobleaching resistance and can reversibly respond to intracellular biothiols/ferric ion with high temporal resolution. The 8 h real-time imaging of living cells was employed to track the fluctuation of biothiols, showing the change of redox status in ferroptosis. In addition, release of ferric ions in cells was monitored. The real-time imaging of depletion of biothiols and release of ferric ion in cells indicates the GCDs-probe can monitor how the ferroptosis regulates redox status in biothiols and ferric metabolism.
Transcriptome analysis reveals GPNMB as a potential therapeutic target for gastric cancer.
Ren Feifei,Zhao Qitai,Liu Bin,Sun Xiangdong,Tang Youcai,Huang Huang,Mei Lu,Yu Yong,Mo Hui,Dong Haibin,Zheng Pengyuan,Mi Yang
Journal of cellular physiology
Gastric cancer has the fifth highest incidence of disease and is the third leading cause of cancer-associated mortality in the world. The etiology of gastric cancer is complex and needs to be fully elucidated. Thus, it is necessary to explore potential pathogenic genes and pathways that contribute to gastric cancer. Gene expression profiles of the GSE33335 and GSE54129 datasets were downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were compared and identified using R software. The DEGs were then subjected to gene set enrichment analysis and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Survival analyses based on The Cancer Genome Atlas database were used to further screen the essential DEGs. A knockdown assay was performed to determine the function of the candidate gene in gastric cancer. Finally, the association between the candidate gene and immune-related genes was investigated. We found that GPNMB serves as an essential gene, with a high expression level, and predicts a worse outcome of gastric cancer. Knockdown of GPNMB inhibited gastric cancer cell proliferation and migration. In addition, GPNMB may augment the immunosuppressive ability of gastric cancer by recruiting immunosuppressive cells and promoting immune cell exhaustion through PI3K/AKT/CCL4 signaling axis. Collectively, these data suggest that GPNMB acts as an important positive mediator of tumor progression in gastric cancer, and GPNMB could exert multimodality modulation of gastric cancer-mediated immune suppression.
Nanoparticles guided drug delivery and imaging in gastric cancer.
Nagaraju Ganji Purnachandra,Srivani Gowru,Dariya Begum,Chalikonda Gayathri,Farran Batoul,Behera Santosh Kumar,Alam Afroz,Kamal Mohammad Amjad
Seminars in cancer biology
Gastric cancer represents a deadly malignancy worldwide, yet current therapeutic regimens remain ineffective. Nanoparticle (NP) -based solutions could allow the design of novel therapeutic methods to eliminate this fatal disease. NPs typically carry out a significant role in multifunctional, multimodal imaging, and drug delivery carriers. In the recent decade, they have emerged as candidate approaches for the design of novel treatment strategies. Tumor nanotherapeutics characteristically possess various distinct advantages compared to conventional anti-cancer medications, which suffer from nonspecific bio-distribution, low solubility, and poor bioavailability. In this review, we will discuss the application of NPs in diagnosis and controlled drug delivery in gastric cancer (GC). We will focus on various NPs-based strategies employed against GC.
Update on gastric cancer treatments and gene therapies.
Biagioni Alessio,Skalamera Ileana,Peri Sara,Schiavone Nicola,Cianchi Fabio,Giommoni Elisa,Magnelli Lucia,Papucci Laura
Cancer metastasis reviews
Gastric cancer is an active topic of clinical and basic research due to high morbidity and mortality. To date, gastrectomy and chemotherapy are the only therapeutic options for gastric cancer patients, but drug resistance, either acquired or primary, is the main cause for treatment failure. Differences in development and response to cancer treatments have been observed among ethnically diverse GC patient populations. In spite of major incidence, GC Asian patients have a significantly better prognosis and response to treatments than Caucasian ones due to genetic discordances between the two populations. Gene therapy could be an alternative strategy to overcome such issues and especially CRISPR/Cas9 represents one of the most intriguing gene-editing system. Thus, in this review article, we want to provide an update on the currently used therapies for the treatment of advanced GC. Graphical abstract.
Gastric cancer: a comprehensive review of current and future treatment strategies.
Sexton Rachel E,Al Hallak Mohammed Najeeb,Diab Maria,Azmi Asfar S
Cancer metastasis reviews
Gastric cancer remains a major unmet clinical problem with over 1 million new cases worldwide. It is the fourth most commonly occurring cancer in men and the seventh most commonly occurring cancer in women. A major fraction of gastric cancer has been linked to variety of pathogenic infections including but not limited to Helicobacter pylori (H. pylori) or Epstein Barr virus (EBV). Strategies are being pursued to prevent gastric cancer development such as H. pylori eradication, which has helped to prevent significant proportion of gastric cancer. Today, treatments have helped to manage this disease and the 5-year survival for stage IA and IB tumors treated with surgery are between 60 and 80%. However, patients with stage III tumors undergoing surgery have a dismal 5-year survival rate between 18 and 50% depending on the dataset. These figures indicate the need for more effective molecularly driven treatment strategies. This review discusses the molecular profile of gastric tumors, the success, and challenges with available therapeutic targets along with newer biomarkers and emerging targets.
How Can Gastric Cancer Molecular Profiling Guide Future Therapies?
Corso Simona,Giordano Silvia
Trends in molecular medicine
Gastric cancer is the third greatest global cause of cancer-related deaths. Despite its high prevalence, only recently have comprehensive genomic surveys shed light on its molecular alterations. As surgery is the only curative treatment strategy and chemotherapy has shown limited efficacy, new treatments are urgently needed. Many molecular therapies for gastric cancer have entered clinical trials but-apart from Trastuzumab and Ramucirumab-all have failed. We analyze the current knowledge of the genetic 'landscape' of gastric cancers, elaborating on novel, preclinical approaches. We posit that this knowledge lays the basis for identifying bona fide molecular targets and developing solid therapeutic approaches, requiring accurate patient selection and taking advantage of preclinical models to assist clinical development of novel combination strategies.
Gastric Cancer, Version 3.2016, NCCN Clinical Practice Guidelines in Oncology.
Ajani Jaffer A,D'Amico Thomas A,Almhanna Khaldoun,Bentrem David J,Chao Joseph,Das Prajnan,Denlinger Crystal S,Fanta Paul,Farjah Farhood,Fuchs Charles S,Gerdes Hans,Gibson Michael,Glasgow Robert E,Hayman James A,Hochwald Steven,Hofstetter Wayne L,Ilson David H,Jaroszewski Dawn,Johung Kimberly L,Keswani Rajesh N,Kleinberg Lawrence R,Korn W Michael,Leong Stephen,Linn Catherine,Lockhart A Craig,Ly Quan P,Mulcahy Mary F,Orringer Mark B,Perry Kyle A,Poultsides George A,Scott Walter J,Strong Vivian E,Washington Mary Kay,Weksler Benny,Willett Christopher G,Wright Cameron D,Zelman Debra,McMillian Nicole,Sundar Hema
Journal of the National Comprehensive Cancer Network : JNCCN
Gastric cancer is the fifth most frequently diagnosed cancer and the third leading cause of death from cancer in the world. Several advances have been made in the staging procedures, imaging techniques, and treatment approaches. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer provide an evidence- and consensus-based treatment approach for the management of patients with gastric cancer. This manuscript discusses the recommendations outlined in the NCCN Guidelines for staging, assessment of HER2 overexpression, systemic therapy for locally advanced or metastatic disease, and best supportive care for the prevention and management of symptoms due to advanced disease.
Gastric cancer is highly prevalent in Lynch syndrome patients with atrophic gastritis.
Cho Hourin,Yamada Masayoshi,Sekine Shigeki,Tanabe Noriko,Ushiama Mineko,Hirata Makoto,Ogawa Gakuto,Gotoh Masahiro,Yoshida Teruhiko,Yoshikawa Takaki,Saito Yutaka,Kuchiba Aya,Oda Ichiro,Sugano Kokichi
Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association
BACKGROUND:Although gastric cancer is one of the Lynch syndrome (LS)-related tumors, the clinicopathological features of gastric cancer in patients with LS remain uncertain. To investigate the incidence risk and clinicopathological features of gastric neoplasms in LS, we conducted a retrospective cohort study in Japanese LS patients. METHODS:LS patients with pathogenic mismatch repair (MMR) gene variants were extracted from the LS registry of the National Cancer Center Hospital, Japan. Cumulative risks of gastric neoplasm, including dysplasia and cancer, were estimated using the Kaplan-Meier method. Gastric atrophy was evaluated endoscopically and/or histologically. Immunohistochemical staining for MMR proteins was performed for all available specimens. RESULTS:Of 118 eligible patients, 26 patients were diagnosed with 58 gastric neoplasms. The cumulative incidence of gastric neoplasm was 41.0% (95% confidence interval, 26.9-55.0) at the age of 70. Of these, 13 (50%) patients developed synchronous and/or metachronous multiple gastric neoplasms. Among the 49 gastric neoplasms available for detailed pathological evaluation, all were associated with intestinal metaplasia. Immunohistochemically, 42 (86%) were MMR-deficient. The individuals with gastric atrophy had a significantly higher risk of developing gastric neoplasms compared with those without gastric atrophy (26 cases/54 individuals vs. 0 cases/53 individuals) (P = 0.026). CONCLUSION:LS patients, particularly those with atrophic gastritis, are at high risk of gastric neoplasm and often develop multiple tumors. Endoscopic surveillance for gastric cancer is recommended for LS patients, especially those with atrophic gastritis.
HER-Family Ligands Promote Acquired Resistance to Trastuzumab in Gastric Cancer.
Sampera Aïda,Sánchez-Martín Francisco Javier,Arpí Oriol,Visa Laura,Iglesias Mar,Menéndez Sílvia,Gaye Élisabeth,Dalmases Alba,Clavé Sergi,Gelabert-Baldrich Mariona,Poulsen Thomas Tuxen,Kragh Michael,Bellosillo Beatriz,Albanell Joan,Rovira Ana,Montagut Clara
Molecular cancer therapeutics
Despite the clinical benefit of trastuzumab, eventually all HER2-amplified gastric cancer tumors develop drug resistance. We aimed to identify molecular mechanisms of acquired resistance to trastuzumab in gastric cancer by using well-established cell line-based preclinical models, as well as samples from patients with HER2-positive gastric cancer treated with trastuzumab. We studied trastuzumab resistance in NCI-N87 and OE19, two gastric cancer cell lines that overexpress HER2 receptor and are trastuzumab sensitive. Differences at protein, DNA, and RNA levels between the parental and resistant cells were characterized and functional studies were performed. Paired pre- and post-trastuzumab blood and tissue samples from patients with gastric cancer treated with trastuzumab were analyzed. We found that resistant cells were associated with increased activation of MAPK/ERK and PI3K/mTOR pathways driven by SRC activation. Upstream, resistant cells showed increased coexpression of multiple HER-family ligands that allowed for compensatory activation of alternative HER receptors upon HER2 blockade. Simultaneous inhibition of EGFR, HER2, and HER3 by the novel antibody mixture, Pan-HER, effectively reverted trastuzumab resistance and Similarly, an increase in HER-family ligands was observed in serum and tumor from patients with gastric cancer after trastuzumab therapy. We propose that trastuzumab resistance in gastric cancer is mediated by HER-family ligand upregulation that allows a compensatory activation of HER receptors and maintains downstream signaling activation despite trastuzumab therapy. Resistance is reverted by simultaneous inhibition of EGFR, HER2, and HER3, thereby revealing a potential therapeutic strategy to overcome trastuzumab resistance in patients with gastric cancer.
Cascade reaction-mediated efficient ferroptosis synergizes with immunomodulation for high-performance cancer therapy.
Li Zhaowei,Rong Long
Given that traditional anticancer therapies fail to significantly improve the prognoses, new modalities with high efficiency are urgently needed. Herein, a nanozyme-based formulation, which synergized efficient ferroptosis with immunomodulation for high-performance cancer therapy, was constructed. Specifically, ultrasmall CaO and FeO nanoparticles (NPs) were co-loaded onto dendritic mesoporous silica nanoparticles (DMSN) followed by coating with the pH-responsive membrane, which could not only prevent the leakage of the cargos but also realize tumor-specific release. After intravenous injection, the H ions in a weak acidic microenvironment triggered the cascade reaction by reacting with CaO and produced abundant HO in the tumor tissue. Subsequently, the produced HO was catalyzed into toxic hydroxyl radicals (˙OH) through a Fenton-like reaction mediated by FeO NPs and induced ferroptosis, which promoted the release of tumor-associated antigens and generated an immunogenic tumor microenvironment (TME). Furthermore, immunomodulation was achieved by the polarization of tumor-associated macrophages (TAMs) induced by pH changes. The efficient ferroptosis and immunomodulation cooperatively paved the way for the inhibition of tumors. Beyond the inhibition of the primary tumor, the formulation could also efficiently provoke the immune response to exert a potent anticancer effect through combining with an immune checkpoint blockade. After being co-loaded with aCD47, the phagocytes could be stimulated and enhance the uptake efficiency of the tumor antigens to realize efficient immunotherapy with few abnormalities. Our approach thus offers a versatile formulation to realize the synergism of ferroptosis and immunomodulation/immunotherapy for high-performance cancer therapy.
Discovery of a novel ferroptosis inducer-talaroconvolutin A-killing colorectal cancer cells in vitro and in vivo.
Xia Yong,Liu Shuzhi,Li Changlin,Ai Zhiying,Shen Wenzhi,Ren Wenqi,Yang Xiaolong
Cell death & disease
Ferropotsis is among the most important mechanisms of cancer suppression, which could be harnessed for cancer therapy. However, no natural small-molecule compounds with cancer inhibitory activity have been identified to date. In the present study, we reported the discovery of a novel ferroptosis inducer, talaroconvolutin A (TalaA), and the underlying molecular mechanism. We discovered that TalaA killed colorectal cancer cells in dose-dependent and time-dependent manners. Interestingly, TalaA did not induce apoptosis, but strongly triggered ferroptosis. Notably, TalaA was significantly more effective than erastin (a well-known ferroptosis inducer) in suppressing colorectal cancer cells via ferroptosis. We revealed a dual mechanism of TalaA' action against cancer. On the one hand, TalaA considerably increased reactive oxygen species levels to a certain threshold, the exceeding of which induced ferroptosis. On the other hand, this compound downregulated the expression of the channel protein solute carrier family 7 member 11 (SLC7A11) but upregulated arachidonate lipoxygenase 3 (ALOXE3), promoting ferroptosis. Furthermore, in vivo experiments in mice evidenced that TalaA effectively suppressed the growth of xenografted colorectal cancer cells without obvious liver and kidney toxicities. The findings of this study indicated that TalaA could be a new potential powerful drug candidate for colorectal cancer therapy due to its outstanding ability to kill colorectal cancer cells via ferroptosis induction.
Ferroptosis Promotes Photodynamic Therapy: Supramolecular Photosensitizer-Inducer Nanodrug for Enhanced Cancer Treatment.
Zhu Ting,Shi Leilei,Yu Chunyang,Dong Yabing,Qiu Feng,Shen Lingyue,Qian Qiuhui,Zhou Guoyu,Zhu Xinyuan
The noninvasive nature of photodynamic therapy (PDT) enables the preservation of organ function in cancer patients. However, PDT is impeded by hypoxia in the tumor microenvironment (TME) caused by high intracellular oxygen (O) consumption and distorted tumor blood vessels. Therefore, increasing oxygen generation in the TME would be a promising methodology for enhancing PDT. Herein, we proposed a concept of ferroptosis-promoted PDT based on the biochemical characteristics of cellular ferroptosis, which improved the PDT efficacy significantly by producing reactive oxygen species (ROS) and supplying O sustainably through the Fenton reaction. In contrast to traditional strategies that increase O based on decomposition of limited concentration of hydrogen peroxide (HO), our methodology could maintain the concentration of HO and O through the Fenton reaction. : For its association with sensitivity to ferroptosis, solute carrier family 7 member 11 (SLC7A11) expression was characterized by bioinformatics analysis and immunohistochemistry of oral tongue squamous cell carcinoma (OTSCC) specimens. Afterwards, the photosensitizer chlorin e6 (Ce6) and the ferroptosis inducer erastin were self-assembled into a novel supramolecular Ce6-erastin nanodrug through hydrogen bonding and π-π stacking. Then, the obtained Ce6-erastin was extensively characterized and its anti-tumor efficacy towards OTSCC was evaluated both and . : SLC7A11 expression is found to be upregulated in OTSCC, which is a potential target for ferroptosis-mediated OTSCC treatment. Ce6-erastin nanoparticles exhibited low cytotoxicity to normal tissues. More significantly, The over-accumulated intracellular ROS, increased O concentration and inhibited SLC7A11 expression lead to enhanced toxicity to CAL-27 cells and satisfactory antitumor effects to xenograft tumour mouse model upon irradiation. : Our ferroptosis promoted PDT approach markedly enhances anticancer actions by relieving hypoxia and promoting ROS production, thereby our work provides a new approach for overcoming hypoxia-associated resistance of PDT in cancer treatment.
Ferroptosis: An emerging approach for targeting cancer stem cells and drug resistance.
Elgendy Sara M,Alyammahi Shatha K,Alhamad Dima W,Abdin Shifaa M,Omar Hany A
Critical reviews in oncology/hematology
Resistance to chemotherapeutic agents remains a major challenge in the fierce battle against cancer. Cancer stem cells (CSCs) are a small population of cells in tumors that possesses the ability to self-renew, initiate tumors, and cause resistance to conventional anticancer agents. Targeting this population of cells was proven as a promising approach to eliminate cancer recurrence and improve the clinical outcome. CSCs are less susceptible to death by classical anticancer agents inducing apoptosis. CSCs can be eradicated by ferroptosis, which is a non-apoptotic-regulated mechanism of cell death. The induction of ferroptosis is an attractive strategy to eliminate tumors due to its ability to selectively target aggressive CSCs. The current review critically explored the crosstalk and regulatory pathways controlling ferroptosis, which can selectively induce CSCs death. In addition, successful chemotherapeutic agents that achieve better therapeutic outcomes through the induction of ferroptosis in CSCs were discussed to highlight their promising clinical impact.
Epigenetic reprogramming of epithelial-mesenchymal transition promotes ferroptosis of head and neck cancer.
Lee Jaewang,You Ji Hyeon,Kim Min-Su,Roh Jong-Lyel
Ferroptosis is a newly defined form of cell death induced by iron-dependent accumulation of lethal lipid peroxidation. Ferroptosis represent a therapeutic strategy to suppress therapy-resistant cancer cells with more property of epithelial-mesenchymal transition (EMT). However, epigenetic reprogramming of EMT has been rarely studied in the context of ferroptosis susceptibility. Therefore, we examined the therapeutic potentiality of EMT epigenetic reprogramming in promoting ferroptosis in head and neck cancer (HNC) cells. The effects of ferroptosis inducers and EMT inhibition or induction were tested in HNC cell lines and mouse tumor xenograft models. These effects were analyzed concerning cell viability and death, lipid reactive oxygen species and iron production, labile iron pool, glutathione contents, NAD/NADH levels, and mRNA/protein expression. Cell density and the expression levels of E-cadherin, vimentin, and ZEB1 were associated with the different susceptibility to ferroptosis inducers. CDH1 silencing or ZEB1 overexpression increased the susceptibility to ferroptosis, whereas CDH overexpression or ZEB1 silencing decreased the susceptibility, in vitro and in vivo. Histone deacetylase SIRT1 gene silencing or pharmacological inhibition by EX-527 suppressed EMT and consequently decreased ferroptosis, whereas SIRT inducers, resveratrol and SRT1720, increased ferroptosis. MiR-200 family inhibitors induced EMT and increased ferroptosis susceptibility. In HNC cells with low expression of E-cadherin, the treatment of 5-azacitidine diminished the hypermethylation of CDH1, resulting in increased E-cadherin expression and decreased ferroptosis susceptibility. Our data suggest that epigenetic reprogramming of EMT contributes to promoting ferroptosis in HNC cells.
Platelet Membrane-Camouflaged Magnetic Nanoparticles for Ferroptosis-Enhanced Cancer Immunotherapy.
Jiang Qin,Wang Kuang,Zhang Xingyu,Ouyang Boshu,Liu Haixia,Pang Zhiqing,Yang Wuli
Small (Weinheim an der Bergstrasse, Germany)
Although cancer immunotherapy has emerged as a tremendously promising cancer therapy method, it remains effective only for several cancers. Photoimmunotherapy (e.g., photodynamic/photothermal therapy) could synergistically enhance the immune response of immunotherapy. However, excessively generated immunogenicity will cause serious inflammatory response syndrome. Herein, biomimetic magnetic nanoparticles, Fe O -SAS @ PLT, are reported as a novel approach to sensitize effective ferroptosis and generate mild immunogenicity, enhancing the response rate of non-inflamed tumors for cancer immunotherapy. Fe O -SAS@PLT are built from sulfasalazine (SAS)-loaded mesoporous magnetic nanoparticles (Fe O ) and platelet (PLT) membrane camouflage and triggered a ferroptotic cell death via inhibiting the glutamate-cystine antiporter system X pathway. Fe O -SAS @ PLT-mediated ferroptosis significantly improves the efficacy of programmed cell death 1 immune checkpoint blockade therapy and achieves a continuous tumor elimination in a mouse model of 4T1 metastatic tumors. Proteomics studies reveal that Fe O -SAS @ PLT-mediated ferroptosis could not only induce tumor-specific immune response but also efficiently repolarize macrophages from immunosuppressive M2 phenotype to antitumor M1 phenotype. Therefore, the concomitant of Fe O -SAS @ PLT-mediated ferroptosis with immunotherapy are expected to provide great potential in the clinical treatment of tumor metastasis.
p53 Suppresses Metabolic Stress-Induced Ferroptosis in Cancer Cells.
Tarangelo Amy,Magtanong Leslie,Bieging-Rolett Kathryn T,Li Yang,Ye Jiangbin,Attardi Laura D,Dixon Scott J
How cancer cells respond to nutrient deprivation remains poorly understood. In certain cancer cells, deprivation of cystine induces a non-apoptotic, iron-dependent form of cell death termed ferroptosis. Recent evidence suggests that ferroptosis sensitivity may be modulated by the stress-responsive transcription factor and canonical tumor suppressor protein p53. Using CRISPR/Cas9 genome editing, small-molecule probes, and high-resolution, time-lapse imaging, we find that stabilization of wild-type p53 delays the onset of ferroptosis in response to cystine deprivation. This delay requires the p53 transcriptional target CDKN1A (encoding p21) and is associated with both slower depletion of intracellular glutathione and a reduced accumulation of toxic lipid-reactive oxygen species (ROS). Thus, the p53-p21 axis may help cancer cells cope with metabolic stress induced by cystine deprivation by delaying the onset of non-apoptotic cell death.
Artemisinin compounds sensitize cancer cells to ferroptosis by regulating iron homeostasis.
Chen Guo-Qing,Benthani Fahad A,Wu Jiao,Liang Deguang,Bian Zhao-Xiang,Jiang Xuejun
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.
Ferroptosis, a novel pharmacological mechanism of anti-cancer drugs.
Su Yanwei,Zhao Bin,Zhou Liangfu,Zhang Zheyuan,Shen Ying,Lv Huanhuan,AlQudsy Luban Hamdy Hameed,Shang Peng
Ferroptosis, a form of regulated cell death, is initiated by oxidative perturbations of the intracellular microenvironment, which is under the constitutive control of glutathione peroxidase 4 (GPX4). Ferrous iron (Fe) accumulation and lipid peroxidation are critical events in the induction of ferroptosis, which is inhibited by iron chelators and lipophilic antioxidants. Ferroptosis terminates in mitochondrial dysfunction and toxic lipid peroxidation. It plays a vital role in inhibiting cancer growth and proliferation. It can be induced in cancer cells, and certain normal cells, by experimental compounds (e.g., erastin, Ras-selective lethal small molecule 3) or clinical drugs. The purpose of this review is to summarize the various drugs (e.g., sulfasalazine, lanperisone, sorafenib, fenugreek (trigonelline), acetaminophen, cisplatin, artesunate, combination of siramesine and lapatinib, ferumoxytol, and salinomycin (ironomycin)) that could induce ferroptosis in cancer cells and provide an overview of current knowledge regarding the mechanisms underlying ferroptosis. In future, we anticipate the development of more ferroptosis-inducing drugs, and the availability of such drugs for the clinical treatment of cancer.
Ferroptosis-driven nanotherapeutics for cancer treatment.
Shan Xinzhu,Li Shumeng,Sun Bingjun,Chen Qin,Sun Jin,He Zhonggui,Luo Cong
Journal of controlled release : official journal of the Controlled Release Society
The clinical efficacy of existing cancer therapies is still far from satisfactory. There is an urgent need to integrate the emerging biomedical discovery and technological innovation with traditional therapies. Ferroptosis, a non-apoptotic programmed cell death modality, has attracted remarkable attention as an emerging therapeutic target for cancer treatment, especially with the burgeoning bionanotechnology. Given the rapid progression in ferroptosis-driven cancer nanotherapeutics, we intend to outline the latest advances in this field at the intersection of ferroptosis and bionanotechnology. First, the research background of ferroptosis and nanotherapeutics is briefly introduced to illustrate the feasibility of ferroptosis-driven nanotherapeutics for cancer therapy. Second, the emerging nanotherapeutics developed to facilitate ferroptosis of tumor cells are overviewed, including promotion of the Fenton reaction, inhibition of cellular glutathione peroxidase 4 (GPX-4), and exogenous regulation of lipid peroxidation. Moreover, ferroptosis-based combination therapeutics are discussed, including the emerging nanotherapeutics combining ferroptosis with tumor imaging, phototherapy, chemotherapy and immunomodulation. Finally, the future expectations and challenges of ferroptosis-driven nanotherapeutics in clinical cancer therapy are spotlighted.
Ferroptosis: Final destination for cancer?
Ye Zeng,Liu Wensheng,Zhuo Qifeng,Hu Qiangsheng,Liu Mengqi,Sun Qiqing,Zhang Zheng,Fan Guixiong,Xu Wenyan,Ji Shunrong,Yu Xianjun,Qin Yi,Xu Xiaowu
Ferroptosis is a recently defined, non-apoptotic, regulated cell death (RCD) process that comprises abnormal metabolism of cellular lipid oxides catalysed by iron ions or iron-containing enzymes. In this process, a variety of inducers destroy the cell redox balance and produce a large number of lipid peroxidation products, eventually triggering cell death. However, in terms of morphology, biochemistry and genetics, ferroptosis is quite different from apoptosis, necrosis, autophagy-dependent cell death and other RCD processes. A growing number of studies suggest that the relationship between ferroptosis and cancer is extremely complicated and that ferroptosis promises to be a novel approach for the cancer treatment. This article primarily focuses on the mechanism of ferroptosis and discusses the potential application of ferroptosis in cancer therapy.