title: Selective tumor cell killing by triptolide in p53 wild-type and p53 mutant ovarian carcinomas.
abstract: Triptolide is a traditional Chinese medicinal herb-derived antineoplastic agent. However, its antitumor activity against gynecologic carcinomas has not yet been well described. It is the purpose of this article to investigate the effect and mechanism of triptolide in human ovarian cancer using both A2780 (p53 wild) and OVCAR-3 (p53 mutated) cells. Our results showed that triptolide exerted a potent inhibitory effect on the growth and proliferation of both cell lines in a dose- and time-dependent manner and that the effect was independent of the expression of p53. In contrast, triptolide had only a marginal cytotoxicity in noncancerous ovary cells, lung fibroblast cells, and macrophage cells, indicating differential inhibitory effects of the drug on cell growth between ovarian cancer cells and normal tissue cells. Exposure of the ovarian cancer cells to triptolide induced apoptosis, as evaluated by annexin V/propidium iodide-labeled flow cytometry. Triptolide-induced apoptosis was accompanied by cytochrome c release and caspase-3 activation and was associated with downregulation of Bcl-2 and upregulation of Bax. Cell cycle analysis demonstrated that treatment with triptolide induced cell cycle S phase arrest in A2780 cells and G2/M phase arrest in OVCAR-3 cells. Further detection by Western blotting revealed that the cell cycle arrest by triptolide in both cell lines occurred in concert with increased expression of p21(CIP1/WAF1). This study shows that triptolide selectively kills ovarian cancer cells with different p53 status predominantly through regulating the coordinate and dynamic cellular processes of proliferation and apoptosis, thereby making it a promising chemotherapeutic agent against a broad spectrum of ovarian carcinomas.
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430072, China.
authors.forename: Jianyuan
authors.initials: J
authors.lastname: Wu
authors.forename: Qingdi Quentin
authors.initials: QQ
authors.lastname: Li
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhou
authors.forename: Yinying
authors.initials: Y
authors.lastname: Lu
authors.forename: Jueli M
authors.initials: JM
authors.lastname: Li
authors.forename: Yao
authors.initials: Y
authors.lastname: Ma
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Tingting
authors.initials: T
authors.lastname: Fu
authors.forename: Xingjiang
authors.initials: X
authors.lastname: Gong
authors.forename: Michael
authors.initials: M
authors.lastname: Weintraub
authors.forename: Shuangchan
authors.initials: S
authors.lastname: Wu
authors.forename: Hong
authors.initials: H
authors.lastname: Ding
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology; D005260:Female; D016158:Genes, p53; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010616:Phenanthrenes / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; C494826:BAX protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C001899:triptolide; D020169:Caspases