Selective tumor cell killing by triptolide in p53 wild-type and p53 mutant ovarian carcinomas

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• 作者：Jianyuan Wu (1)
  Qingdi Quentin Li (2)
  Huiping Zhou (3)
  Yinying Lu (4)
  Jueli M. Li (5)
  Yao Ma (1)
  Li Wang (1)
  Tingting Fu (1)
  Xingjiang Gong (1)
  Michael Weintraub (2)
  Shuangchan Wu (1)
  Hong Ding (1) (6)
  
• 关键词：Triptolide ; Ovarian cancer ; Antitumor drug ; Apoptosis ; Cell cycle ; p53
• 刊名：Medical Oncology
• 出版年：2014
• 出版时间：July 2014
• 年：2014
• 卷：31
• 期：7
• 全文大小：
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• 作者单位：Jianyuan Wu (1)
  Qingdi Quentin Li (2)
  Huiping Zhou (3)
  Yinying Lu (4)
  Jueli M. Li (5)
  Yao Ma (1)
  Li Wang (1)
  Tingting Fu (1)
  Xingjiang Gong (1)
  Michael Weintraub (2)
  Shuangchan Wu (1)
  Hong Ding (1) (6)
  
  1. Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430072, China
  2. National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
  3. Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, 23298, USA
  4. Center for Therapeutic Research of Hepatocellular Carcinoma, Beijing 302 Hospital, Beijing, 100039, China
  5. University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA
  6. Department of Pharmacology, Hubei University of Science and Technology, Xianning, 437100, China
  
• ISSN：1559-131X

文摘

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 p21CIP1/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.