PubMedPro - 齐墩果酸

Inhibition of tumor progression by naturally occurring terpenoids. Kuttan Girija,Pratheeshkumar Poyil,Manu Kanjoormana Aryan,Kuttan Ramadasan Pharmaceutical biology CONTEXT:Cancer is a major public health problem in India and many other parts of the world. Its two main characteristics are uncontrolled cell growth and metastasis. Natural products represent a rich source of compounds that have found many applications in various fields of medicines and therapy including cancer therapy. Effective ingredients in several plant-derived medicinal extracts are terpenoid compounds and many terpenes have biological activities and are used for the treatment of human diseases. OBJECTIVES:This review attempted to collect all available published scientific literature of eight naturally occurring terpenoids and their effect on inhibition of tumor progression. METHODS:The present review is about eight potent naturally occurring terpenoids that have been studied for their pharmacological properties in our lab and this review includes 130 references compiled from all major databases. RESULTS:Literature survey revealed that triterpenoids, such as glycyrrhizic acid, ursolic acid, oleanolic acid, and nomilin, the diterpene andrographolide, and the monoterpenoids like limonene and perillic acid had shown immunomodulatory and antitumor activities. All of them could induce apoptosis in various cancer cells by activating various proapoptotic signaling cascades. Many of these terpenoids found to inhibit metastatic progression and tumor-induced angiogenesis. The molecular mechanisms that involved in these activities include inhibition of various oncogenic and anti-apoptotic signaling pathways and suppression or nuclear translocation of various transcription factors including nuclear factor kappa B (NF-κB). CONCLUSION:The chemopreventive and chemoprotective effects of these compounds point toward their possible role in modern anticancer therapies. 10.3109/13880209.2011.559476

Triterpenoids as new promising anticancer drugs. Petronelli Alessia,Pannitteri Gaetano,Testa Ugo Anti-cancer drugs Triterpenoids are structurally diverse organic compounds, characterized by a basic backbone modified in multiple ways, allowing the formation of more than 20 000 naturally occurring triterpenoid varieties. Several triterpenoids, including ursolic and oleanolic acid, betulinic acid, celastrol, pristimerin, lupeol, and avicins possess antitumor and anti-inflammatory properties. To improve antitumor activity, some synthetic triterpenoid derivatives have been synthesized, including cyano-3,12-dioxooleana-1,9 (11)-dien-28-oic (CDDO), its methyl ester (CDDO-Me), and imidazolide (CDDO-Im) derivatives. Of these, CDDO, CDDO-Me, and betulinic acid have shown promising antitumor activities and are presently under evaluation in phase I studies. Triterpenoids are highly multifunctional and the antitumor activity of these compounds is measured by their ability to block nuclear factor-kappaB activation, induce apoptosis, inhibit signal transducer, and activate transcription and angiogenesis. 10.1097/CAD.0b013e328330fd90

Modulation of Tumour-Related Signaling Pathways by Natural Pentacyclic Triterpenoids and their Semisynthetic Derivatives. Markov Andrey V,Zenkova Marina A,Logashenko Evgeniya B Current medicinal chemistry Pentacyclic triterpenoids are a large class of natural isoprenoids that are widely biosynthesized in higher plants. These compounds are potent anticancer agents that exhibit antiproliferative, antiangiogenic, antiinflammatory and proapoptotic activities. Although their effects on multiple pathways have been reported, unifying mechanisms of action have not yet been established. To date, a huge number of semisynthetic derivatives have been synthesized in different laboratories on the basis of triterpenoid scaffolds, and many have been assayed for their biological activities. The present review focuses on natural triterpenoids of the oleanane-, ursane- and lupane-types and their semisynthetic derivatives. Here, we summarize the diverse cellular and molecular targets of these compounds and the signal pathways involved in the performance of their antitumour actions. Among the most relevant mechanisms involved are cell cycle arrest, apoptosis and autophagy triggered by the effect of triterpenoids on TGF-β and HER cell surface receptors and the downstream PI3KAkt- mTOR and IKK/NF-kB signaling axis, STAT3 pathway and MAPK cascades. 10.2174/0929867324666170112115313

Inhibition of cytochrome P450 activities by oleanolic acid and ursolic acid in human liver microsomes. Life sciences Oleanolic acid (OA) and ursolic acid (UA), triterpene acids having numerous pharmacological activities including anti-inflammatory, anti-cancer, and hepato-protective effects, were tested for their ability to modulate the activities of several cytochrome P450 (CYP) enzymes using human liver microsomes. OA competitively inhibited CYP1A2-catalyzed phenacetin O-deethylation and CYP3A4-catalyzed midazolam 1-hydroxylation, the major human drug metabolizing CYPs, with IC50 (Ki) values of 143.5 (74.2) microM and 78.9 (41.0) microM, respectively. UA competitively inhibited CYP2C19-catalyzed S-mephenytoin 4'-hydroxylation with an IC50 (Ki) value of 119.7 (80.3) microM. However, other CYPs tested showed no or weak inhibition by both OA and UA. The present study demonstrates that OA and UA have inhibitory effects on CYP isoforms using human liver microsomes. It is thus likely that consumption of herbal medicines containing OA or UA, or administration of OA or UA, can cause drug interactions in humans when used concomitantly with drugs that are metabolized primarily by CYP isoforms. In addition, it appears that the inhibitory effect of OA on CYP1A2 is, in part, related to its anti-inflammatory and anticancer activities. 10.1016/j.lfs.2003.10.020

Synthesis, selective cancer cytotoxicity and mechanistic studies of novel analogs of lantadenes. Tailor Navin Kumar,Jaiswal Varun,Lan San Swee,Lee Hong Boon,Sharma Manu Anti-cancer agents in medicinal chemistry The ring A and D substituted analogs of pentacyclic triterpenoid Lantadene A (1) and B (2) were synthesized and evaluated for in vitro anticancer activity against four human cancer cell lines (HL-60, MCF-7, A549 and HCT-116). Analogs 3, 4, 7 and 8 showed enhanced inhibitory activity as compared with 1 and 2. These analogs were found more active than standard drug cisplatin with selective toxicity towards cancer cells and were inactive against normal cells (VERO). Furthermore, the mechanistic studies to investigate the effects of the new compounds on Akt protein in lung cancer cell line A549 and the NF-κB signalling pathway suggested that the compounds may exert their inhibitory activity on cancer cells through inhibition of both Akt and NF-κB activation. The docking studies of most potent analog (7) with 3D crystal structure of the nuclear factor kappa-B (NF-κB) P50 homodimer (PDB ID: 1NFK) revealed that carbonyl group of ester side chain and C-28 carboxylic acid groups were mainly involved in hydrogen bonding interaction. The oleanane frameworks was involved in strong hydrophobic interaction with amino acid phenylalanine and structure of lead compound have the potential to be developed as potent NF-κB inhibitor and anticancer agent. 10.2174/18715206113139990127

Synthesis and Evaluation of Anticancer Activities of Novel C-28 Guanidine-Functionalized Triterpene Acid Derivatives. Spivak Anna,Khalitova Rezeda,Nedopekina Darya,Dzhemileva Lilya,Yunusbaeva Milyausha,Odinokov Victor,D'yakonov Vladimir,Dzhemilev Usein Molecules (Basel, Switzerland) Triterpene acids, namely, 20,29-dihydrobetulinic acid (BA), ursolic acid (UA) and oleanolic acid (OA) were converted into C-28-amino-functionalized triterpenoids ⁻, , , and . These compounds served as precursors for the synthesis of novel guanidine-functionalized triterpene acid derivatives ⁻, , and . The influence of the guanidine group on the antitumor properties of triterpenoids was investigated. The cytotoxicity was tested on five human tumor cell lines (Jurkat, K562, U937, HEK, and Hela), and compared with the tests on normal human fibroblasts. The antitumor activities of the most tested guanidine derivatives was lower, than that of corresponding amines, but triterpenoids with the guanidine group were less toxic towards human fibroblasts. The introduction of the tris(hydroxymethyl)aminomethane moiety into the molecules of triterpene acids markedly enhanced the cytotoxic activity of the resulting conjugates , , , and , irrespective of the triterpene skeleton type. The dihydrobetulinic acid amine , its guanidinium derivative and guanidinium derivatives of ursolic and oleanolic acids and were selected for extended biological investigations in Jurkat cells, which demonstrated that the antitumor activity of these compounds is mediated by induction of cell cycle arrest at the S-phase and apoptosis. 10.3390/molecules23113000

Oleanolic acid and ursolic acid: research perspectives. Journal of ethnopharmacology Oleanolic acid and ursolic acid are ubiquitous triterpenoids in plant kingdom, medicinal herbs, and are integral part of the human diet. During the last decade over 700 research articles have been published on their research, reflecting tremendous interest and progress in our understanding of these triterpenoids. This included the isolation and purification of these tritepernoids from various plants and herbs, the chemical modifications to make more effective and water soluble derivatives, the pharmacological research on their beneficial effects, the toxicity studies, and the clinical use of these triterpenoids in various diseases including anticancer chemotherapies. A briefly commentary is attempted here for their research perspectives. 10.1016/j.jep.2005.05.024

Selective in vitro anti-melanoma activity of ursolic and oleanolic acids. Toxicology mechanisms and methods Products of natural origin have become important agents in the treatment of cancer, and the active principles of natural sources could be used in combination with chemotherapeutic agents to increase their effects and to minimize their toxicity. Oleanolic (OA) and ursolic (UA) acids are intensely studied for their promising anticancer potential. The aim of this study was focused on the in vitro toxicological effects induced by UA and OA human mesenchymal stem cells and on melanoma, one of the most frequent cancers whose incidence is increasing every year. The two compounds were tested for their cytotoxic, cell cycle arrest and pro-apoptotic effects on melanoma cells (A375 and B164A5) and mesenchymal stem cells. UA exerted a cytotoxic effect in a dose-dependent manner on melanoma cells, while OA's activity has been shown to be low or moderate. Both compounds produced alterations of the cell cycle, arresting cells in the G0/G1 phase. Furthermore, UA induced significant apoptosis through the bcl-2 genes family pathway, with the decrease of the bcl-2 gene expression. The two compounds exerted selective effects on melanoma cells with no effects on human mesenchymal stem cells. The presented results reveal the anticancer potential of UA on melanoma cells, with no detectable toxicity on the mesenchymal stem cells. 10.1080/15376516.2017.1373881

Enhancing anticancer activity through the combination of bioreducing agents and triterpenes. Bednarczyk-Cwynar Barbara,Ruszkowski Piotr,Jarosz Tomasz,Krukiewicz Katarzyna Future medicinal chemistry AIM:Triterpenes are natural compounds, whose wide biological activity predestines them for application as promising new chemotherapeutics. In this paper, we report the results of our investigations into the substitution of oleanolic acid with aromatic and nitroaromatic moieties acting as bioreducing agents. RESULTS:The process of reduction of nitro groups was investigated through cyclic voltammetry, UV-Vis and electron paramagnetic resonance spectroelectrochemistry. The cytotoxic activity against selected cancer cell lines was determined, showing a significant increase in cytotoxicity when the triterpene is equipped with a nitroaromatic moiety. CONCLUSION:We believe this approach to the functionalization is promising in terms of enhancing anticancer activity. We also indicate electrochemical techniques as advantageous preclinical screening methods for the identification of cytotoxic agents. 10.4155/fmc-2017-0154

Oleanane-, ursane-, and quinone methide friedelane-type triterpenoid derivatives: Recent advances in cancer treatment. Salvador Jorge A R,Leal Ana S,Valdeira Ana S,Gonçalves Bruno M F,Alho Daniela P S,Figueiredo Sandra A C,Silvestre Samuel M,Mendes Vanessa I S European journal of medicinal chemistry Natural pentacyclic triterpenoids (PTs) have been often reported to exhibit a wide range of biological activities. Among them, the anticancer and anti-inflammatory activities are the most studied. Over the last two decades, the number of publications reporting the anticancer effects of PTs has risen exponentially, reflecting the increasing interest in these natural products for the development of new antineoplastic drugs. Among of the most investigated PTs regarding their anticancer properties are oleanane-, ursane and friedelane-types, including oleanolic, glycyrrhetinic, ursolic and asiatic acids, and celastrol, among others. The extensive research in this field shows that the anticancer effects of PTs are mediated by several mechanisms, as they modulate a diverse range of molecular targets and signaling pathways, involved in cancer cell proliferation and survival. Considering the anticancer potential of this class of compounds, a number of semisynthetic derivatives has been synthetized aiming to improve their therapeutic activity and pharmacokinetic properties, and decrease their toxicity. Some of these new semisynthetic derivatives have shown improved anticancer activity in various cancer cell lines and animal models compared with the parent compound. Moreover, some of these compounds have been assessed in clinical trials, proving to be safe for human use. This review updates the most recent findings on the semisynthetic derivatives of oleanane-, ursane- and quinone methide friedelane-type PTs with anticancer activity. A brief introduction concerning the PTs and their anticancer activity is given, and the main semisynthetic modifications that have been performed between 2012 and early 2017 are reviewed and discussed. 10.1016/j.ejmech.2017.07.013

Oleanolic acid induces p53-dependent apoptosis the ERK/JNK/AKT pathway in cancer cell lines in prostatic cancer xenografts in mice. Oncotarget We evaluated oleanolic acid (OA)-induced anti-cancer activity, apoptotic mechanism, cell cycle status, and MAPK kinase signaling in DU145 (prostate cancer), MCF-7 (breast cancer), U87 (human glioblastoma), normal murine liver cell (BNL CL.2) and human foreskin fibroblast cell lines (Hs 68). The IC50 values for OA-induced cytotoxicity were 112.57 in DU145, 132.29 in MCF-7, and 163.60 in U87 cells, respectively. OA did not exhibit toxicity in BNL CL. 2 and Hs 68 cell lines in our experiments. OA, at 100 µg/mL, increased the number of apoptotic cells to 27.0% in DU145, 27.0% in MCF-7, and 15.7% in U87, when compared to control cells. This enhanced apoptosis was due to increases in p53, cytochrome c, Bax, PARP-1 and caspase-3 expression in DU145, MCF-7 and U87 cell lines. OA-treated DU145 cells were arrested in G2 because of the activation of p-AKT, p-JNK, p21 and p27, and the decrease in p-ERK, cyclin B1 and CDK2 expression; OA-treated MCF-7 cells were arrested in G1 owing to the activation of p-JNK, p-ERK, p21, and p27, and the decrease in p-AKT, cyclin D1, CDK4, cyclin E, and CDK2; and OA-treated U87 cells also exhibited G1 phase arrest caused by the increase in p-ERK, p-JNK, p-AKT, p21, and p27, and the decrease in cyclin D1, CDK4, cyclin E and CDK2. Thus, OA arrested the cell cycle at different phases and induced apoptosis in cancer cells. These results suggested that OA possibly altered the expression of the cell cycle regulatory proteins differently in varying types of cancer. 10.18632/oncotarget.25316

Radiosensitizing effect of oleanolic acid on tumor cells through the inhibition of GSH synthesis in vitro. Wang Juan,Yu Maohu,Xiao Linlin,Xu Shiguo,Yi Qiyi,Jin Wensen Oncology reports Oleanolic acid (OA) is a natural pentacyclic triterpenoid that has been used in traditional medicine as an anticancer and anti-inflammatory agent. The aim of our study was to investigate whether or not OA increases the radiosensivity of tumor cells, and the relative mechanism was also investigated. Clonogenic assay was used to observe the radiosensitivity of C6 and A549 cells following different treatments. The alteration of intracellular DNA damage was determined using a micronucleus (MN) assay. In order to identify the mechanism of OA-mediated radiosensitization of tumor cells, the levels of glutathione (GSH) in irradiated cells following various pretreatments were determined using glutathione reductase/5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB) recycling assay. Under the same condition, the activities of γ-glutamylcysteine synthetase (γ-GCS) and GSH synthase (GSS), both key enzymes for GSH synthesis, were detected using appropriate methods. In order to confirm the radiosensitizing effect of OA on cancer cells by attenuating GSH, N-acetylcysteine (NAC) was added to cells in culture for 12 h before irradiation. The results showed that the combined treatment of radiation with OA significantly decreased the clonogenic growth of tumor cells and enhanced the numbers of intracellular MN compared to irradiation alone. Furthermore, it was found that the synthesis of cellular GSH was inhibited concomitantly with the downregulation of γ-GCS activity. Therefore, the utilization of OA as a radiosensitizing agent for irradiation-inducing cell death offers a potential therapeutic approach to treat cancer. 10.3892/or.2013.2510

Oleanolic acid suppresses aerobic glycolysis in cancer cells by switching pyruvate kinase type M isoforms. PloS one Warburg effect, one of the hallmarks for cancer cells, is characterized by metabolic switch from mitochondrial oxidative phosphorylation to aerobic glycolysis. In recent years, increased expression level of pyruvate kinase M2 (PKM2) has been found to be the culprit of enhanced aerobic glycolysis in cancer cells. However, there is no agent inhibiting aerobic glycolysis by targeting PKM2. In this study, we found that Oleanolic acid (OA) induced a switch from PKM2 to PKM1, and consistently, abrogated Warburg effect in cancer cells. Suppression of aerobic glycolysis by OA is mediated by PKM2/PKM1 switch. Furthermore, mTOR signaling was found to be inactivated in OA-treated cancer cells, and mTOR inhibition is required for the effect of OA on PKM2/PKM1 switch. Decreased expression of c-Myc-dependent hnRNPA1 and hnRNPA1 was responsible for OA-induced switch between PKM isoforms. Collectively, we identified that OA is an antitumor compound that suppresses aerobic glycolysis in cancer cells and there is potential that PKM2 may be developed as an important target in aerobic glycolysis pathway for developing novel anticancer agents. 10.1371/journal.pone.0091606

Cytotoxicity of oleanolic and ursolic acid derivatives toward hepatocellular carcinoma and evaluation of NF-κB involvement. Bioorganic chemistry Oleanolic and ursolic acids are two ubiquitous isomeric triterpene phytochemicals known for their anticancer activity. A set of derivatives of the two compounds with a modified oxidation state and lipophylicity at C-3 and C-28 positions, were prepared and tested as anticancer agents versus the lines HepG2, Hep3B and HA22T/VGH of hepatocarcinoma, a strongly aggressive tumor that is not responsive toward the standard therapies. New derivatives containing a three carbons side chain on the C-3 position were synthetized in both stereoisomeric forms by the Barbier-Grignard procedure and three of them were found to be active toward all of the three targets. The implication of the transcriptional nuclear factor NF-κB in the mechanism of action was assessed for the more active compounds in the set, as hepatocellular carcinoma (HCC) cyto-types are known to overexpress NF-κB. 10.1016/j.bioorg.2019.103054

Anticancer effect of A-ring or/and C-ring modified oleanolic acid derivatives on KB, MCF-7 and HeLa cell lines. Bednarczyk-Cwynar Barbara,Zaprutko Lucjusz,Ruszkowski Piotr,Hładoń Bogusław Organic & biomolecular chemistry New A-ring or/and C-ring modified methyl oleanolate derivatives were prepared. New simple method of synthesis of 3,12-diketone (3) from methyl oleanonate (2) was worked out. The obtained new compounds were tested for cytotoxic activity on KB, MCF-7 and HeLa cell lines. The derivatives had acetoxy, oxo or hydroxyimino function at the C-3 position and in some cases oxo, hydroxyimino or acyloxyimino group at the C-12 position. Almost all of the compounds showed strong cytotoxic activity, higher than unchanged oleanolic acid. The most active substances turned out to be the derivatives with acyloxyimino function, especially 4 and 8d. 10.1039/c2ob06923g

Oleanolic acid. Pollier Jacob,Goossens Alain Phytochemistry Oleanolic acid (3β-hydroxyolean-12-en-28-oic acid) is a pentacyclic triterpenoid compound with a widespread occurrence throughout the plant kingdom. In nature, the compound exists either as a free acid or as an aglycone precursor for triterpenoid saponins, in which it can be linked to one or more sugar chains. Oleanolic acid and its derivatives possess several promising pharmacological activities, such as hepatoprotective effects, and anti-inflammatory, antioxidant, or anticancer activities. With the recent elucidation of its biosynthesis and the imminent commercialization of the first oleanolic acid-derived drug, the compound promises to remain important for various studies. In this review, the recent progress in understanding the oleanolic acid biosynthesis and its pharmacology are discussed. Furthermore, the importance and potential application of synthetic oleanolic acid derivatives are highlighted, and research perspectives on oleanolic acid are given. 10.1016/j.phytochem.2011.12.022

Oleanolic acid inhibits cell proliferation migration and invasion and induces SW579 thyroid cancer cell line apoptosis by targeting forkhead transcription factor A. Duan Lijun,Yang Zhang,Jiang Xia,Zhang Jianhua,Guo Xuye Anti-cancer drugs Oleanolic acid (OA) is a naturally occurring triterpenoid that possesses antitumor activity against several tumor cell lines. However, the potential mechanism underlying OA-induced thyroid carcinoma cell death is poorly understood. We investigated the biological functions of OA by performing migration, invasion, colony formation, and apoptosis assays on SW579 cells. Forkhead box A1 (FOXA1) expression was used to predict poor prognosis in patients with thyroid carcinoma among the TCGA samples from the UALCAN and gene expression profiling interactive analysis databases. Western blot was used to detect protein expression level. Results revealed that OA inhibited the migration, colony formation, and invasion of thyroid carcinoma cells in a dose-dependent manner. Further investigation verified that OA treatment induced significant apoptosis of thyroid carcinoma cells. Moreover, high FOXA1 expression predicted the poor prognosis of patients with thyroid cancer. The proliferation, migration, and invasion of thyroid carcinoma cells were significantly decreased when FOXA1 was silenced. OA significantly increased Akt phosphorylation and reduced FOXA1 expression in SW579 cells, but only PI3K/Akt inhibitor LY294002 attenuated OA-induced FOXA1 downregulation. Furthermore, Akt overexpression suppressed the FOXA1 expression in SW579 cells. In addition, molecular docking assay revealed that OA possessed high affinity toward FOXA1 with a low binding energy. OA may be a potential chemotherapeutic agent against thyroid carcinoma cells. 10.1097/CAD.0000000000000777

Synthesis and antitumor activities of naturally occurring oleanolic acid triterpenoid saponins and their derivatives. Liu Qingchao,Liu Hongchun,Zhang Lei,Guo Tiantian,Wang Peng,Geng Meiyu,Li Yingxia European journal of medicinal chemistry Twenty-six naturally occurring oleanolic acid saponins and their derivatives, 16 of which were synthesized in this study, were preliminarily evaluated against human cancer cells. From SAR studies, the presence of α-l-rhamnosyl residue at the terminal of both C-3 and C-28 position for oleanolic acid bidesmosides was important to enhance cytotoxicity, and introducing more sugar residues at C3-OH of compound 12 with C-28 carboxylic acid is a favorable modification to ameliorate the anticancer activity. Furthermore, α-l-rhamnosyl moiety linked to C2-OH of the first monosaccharide (α-l-alabinose, β-d-xylose, β-d-galactose or β-d-glucose) in C3-OH of oleanolic acid was helpful to improve the cytotoxicity. According to the predicted log P values, lipophilicity of the synthesized saponins was not an important factor for cytotoxicity. 10.1016/j.ejmech.2013.04.016

Synthesis and cytotoxicity of oleanolic acid trisaccharide saponins. Wang Liming,Wang Zengshang,Su Sheng,Xing Ying,Li Yali,Li Ming,Liu Jiangyun,Yang Shilin Carbohydrate research An array of oleanolic acid-type saponins based on β-hederin has been synthesized in a linear or one-pot manner. The cell viability assays indicate that synthetic saponins show antiproliferation activities in three cancer cell lines with IC values of 2.4-15.1 μM and hederacolchiside A being the most potent. The results demonstrate that the type of terminal monosaccharides and linkage position have apparent effects on cytotoxicities and selectivities of these saponins against cancer cell lines tested. This study is helpful for future development of more potent anticancer leads. 10.1016/j.carres.2017.02.010

Oleanolic acid synthetic oligoglycosides: a review on recent progress in biological activities. Xu Kuo,Chu Fuhao,Li Guoliang,Xu Xin,Wang Penglong,Song Jixiang,Zhou Sen,Lei Haimin Die Pharmazie The natural product oleanolic acid has been widely used for treating hepatopathy in China, whereas its clinical application was confined by poor solubility in water. Inspired by remarkable bioactivities and physical properties of triterpenoid saponins, synthesis and biological evaluation of oleanolic acid oligoglycosides drew considerable attention. In the past several years, chemical efforts were made toward glycosylated modifications of oleanolic acid at C3-OH and C17-COOH, of the carbons at ring A/C, and of the functional groups of oleanolic acid lactone. To provide useful information for further study and applications of oleanolic acid derivatives, a total of 177 oleanolic acid synthetic oligoglycosides and their bioactivities (e.g., antiosteoporosis, antidiabetes, antibacterial, anticancer and hemolytic effects) were reviewed; structure-activity relationships and promising agents are indicated.

Oleanolic acid derivatives for pharmaceutical use: a patent review. Lin Chao,Wen Xiaoan,Sun Hongbin Expert opinion on therapeutic patents INTRODUCTION:Oleanolic acid belongs to the pentacyclic triterpene family. In China, oleanolic acid has been used as an over the counter (OTC) hepatoprotective drug for decades. Oleanolic acid and its derivatives present a wide variety of biological activities, supporting their pharmaceutical uses for multiple diseases. AREAS COVERED:Representative patent publications (1971-2015) covering the preparation, pharmaceutical compositions, and medical uses of oleanolic acid and its derivatives are analyzed, with focus on their anticancer, anti-osteoporosis, anti-obesity, anti-diabetic, lipid-lowering, anti-inflammatory, antioxidant, immune-regulatory, and hepatoprotective effects. A large number of Chinese patents have been given particular attention in this review. EXPERT OPINION:Detailed efficacy studies are highly worth doing to undoubtedly confirm the clinical potential of oleanolic acid and its derivatives. Based on that, it would be critical to identify the key protein targets of the drugs so as to promote drug development and search for new lead compounds. Together, there is a huge potential for drug-repositioning of oleanolic acid, particularly in the areas of metabolic disease and immunological disorders. 10.1080/13543776.2016.1182988

Solid inclusion complexes of oleanolic acid with amino-appended β-cyclodextrins (ACDs): Preparation, characterization, water solubility and anticancer activity. Ren Yufeng,Liu Ying,Yang Zhikuan,Niu Raomei,Gao Kai,Yang Bo,Liao Xiali,Zhang Jihong Materials science & engineering. C, Materials for biological applications Oleanolic acid (OA) is a pentacyclic triterpenoid acid of natural abundance in plants which possesses important biological activities. However, its medicinal applications were severely impeded by the poor water solubility and resultant low bioavailability and potency. In this work, studies on solid inclusion complexes of OA with a series of amino-appended β-cyclodextrins (ACDs) were conducted in order to address this issue. These complexes were prepared by suspension method and were well characterized by NMR, SEM, XRD, TG, DSC and Zeta potential measurement. The 2:1 inclusion mode of ACDs/OA complexes was elucidated by elaborate 2D NMR (ROESY). Besides, water solubility of OA was dramatically promoted by inclusion complexation with ACDs. Moreover, in vitro anticancer activities of OA against human cancer cell lines HepG2, HT29 and HCT116 were significantly enhanced after formation of inclusion complexes, while the apoptotic response results indicated their induction of apoptosis of cancer cells. This could provide a novel approach to development of novel pharmaceutical formulations of OA. 10.1016/j.msec.2016.05.022

Oleanolic Acid Alters Multiple Cell Signaling Pathways: Implication in Cancer Prevention and Therapy. Žiberna Lovro,Šamec Dunja,Mocan Andrei,Nabavi Seyed Fazel,Bishayee Anupam,Farooqi Ammad Ahmad,Sureda Antoni,Nabavi Seyed Mohammad International journal of molecular sciences Nowadays, much attention has been paid to diet and dietary supplements as a cost-effective therapeutic strategy for prevention and treatment of a myriad of chronic and degenerative diseases. Rapidly accumulating scientific evidence achieved through high-throughput technologies has greatly expanded the understanding about the multifaceted nature of cancer. Increasingly, it is being realized that deregulation of spatio-temporally controlled intracellular signaling cascades plays a contributory role in the onset and progression of cancer. Therefore, targeting regulators of oncogenic signaling cascades is essential to prevent and treat cancer. A plethora of preclinical and epidemiological evidences showed promising role of phytochemicals against several types of cancer. Oleanolic acid, a common pentacyclic triterpenoid, is mainly found in olive oil, as well as several plant species. It is a potent inhibitor of cellular inflammatory process and a well-known inducer of phase 2 xenobiotic biotransformation enzymes. Main molecular mechanisms underlying anticancer effects of oleanolic acid are mediated by caspases, 5' adenosine monophosphate-activated protein kinase, extracellular signal-regulated kinase 1/2, matrix metalloproteinases, pro-apoptotic Bax and bid, phosphatidylinositide 3-kinase/Akt1/mechanistic target of rapamycin, reactive oxygen species/apoptosis signal-regulating kinase 1/p38 mitogen-activated protein kinase, nuclear factor-κB, cluster of differentiation 1, CKD4, s6k, signal transducer and activator of transcription 3, as well as aforementioned signaling pathways . In this work, we critically review the scientific literature on the molecular targets of oleanolic acid implicated in the prevention and treatment of several types of cancer. We also discuss chemical aspects, natural sources, bioavailability, and safety of this bioactive phytochemical. 10.3390/ijms18030643

Synthesis of novel oleanolic acid and ursolic acid in C-28 position derivatives as potential anticancer agents. Archives of pharmacal research A series of nitrogen-containing derivatives of oleanolic acid and ursolic acid were prepared by a modification at C-28 position via esterification with 2-hydroxyacetic acid followed by amidation with amines, such as piperazine, N-methylpiperazine, and alkane-1, 2-diamines, alkane-1, 4-diamines, alkane-1, 6-diamines. In vitro antiproliferative activities of the compounds prepared towards MCF-7, Hela and A549 cell lines were evaluated by a MTT method to show that OA-5a, OA-5b, OA-5c and UA-5a showed somewhat improved antiproliferative activities against MCF-7, Hela and A549 cells comparing to that of the positive control, gefitinib. 10.1007/s12272-016-0868-8

Inhibition of cancer cell growth by oleanolic acid in multidrug resistant liver carcinoma is mediated via suppression of cancer cell migration and invasion, mitochondrial apoptosis, G2/M cell cycle arrest and deactivation of JNK/p38 signalling pathway. Gao Chao,Li Xuehua,Yu Shuangshuang,Liang Liang Journal of B.U.ON. : official journal of the Balkan Union of Oncology PURPOSE:Liver cancer accounts for considerable mortality across the globe. The sharp upsurge in the incidence of liver cancer, unavailability of standard treatments and the adverse side effects associated with the existing drugs has made it compulsory to explore novel and more effective anticancer molecules. In this study the anticancer effects of a natural compound oleanolic acid were investigated in vitro. METHODS:The human HepG2 liver cancer cells were treated with various concentrations of oleanolic acid for 24 h. The antiproliferative effects of oleanolic acid were measured by CCK8 cell viability assay. DAPI and annexin V/propidium iodide (PI) assays were employed to examine the induction of apoptosis. Transwell assay was performed to examine the cell migration and invasion. Expression analysis was performed by western blot analysis. RESULTS:The results showed that oleanolic acid decreased the viability of the liver cancer HepG2 cells and exhibited an IC50 of 30 µM. The cytotoxicity of oleanolic acid was also investigated on the normal liver cells AML12 and it was found that oleanolic acid and exerted very low toxic effects on these cells and exhibited an IC50 of 120 µM. Oleanolic acid also caused remarkable changes in the morphology of the HepG2 cells and inhibited their colony formation potential. Flow cytometry indicated oleanolic acid triggered G2/M arrest of the liver HepG2 cancer cells. PI and DAPI staining revealed that oleanolic acid prompted apoptosis of the HepG2 cells. The apoptotic cells increased from 2.2% in control to around 35% at 30 µM concentration. Oleanolic acid also suppressed the migration and invasion of the liver cancer cells via blocking of the JNK/p38 signalling pathway. CONCLUSIONS:The results of the current research revealed that oleanolic acid can be a molecule that may be utilised in the treatment of liver cancer in the future.