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Author Qi, Huan ♦ Zuo, Dai-Ying ♦ Bai, Zhao-Shi ♦ Xu, Jing-Wen ♦ Li, Zeng-Qiang ♦ Shen, Qi-Rong ♦ Wang, Zhi-Wei ♦ Zhang, Wei-Ge ♦ Wu, Ying-Liang
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword APPLIED LIFE SCIENCES ♦ COMPARATIVE EVALUATIONS ♦ HEPATOMAS ♦ IN VITRO ♦ IN VIVO ♦ LIVER ♦ LIVER CELLS ♦ MICROTUBULES ♦ POLYMERIZATION ♦ TOXICITY
Abstract Highlights: • COH-203 exhibits anti-hepatoma effects in vitro and in vivo with low toxicity. • COH-203 inhibits tubulin polymerization. • COH-203 induces mitotic arrest followed by mitotic slippage in BEL-7402 cells. • COH-203 induces p53-dependent senescence in BEL-7402 cells. - Abstract: 5-(3-Hydroxy-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-3H-1, 2-dithiol-3-one (COH-203) is a novel synthesized analogue of combretastatin A-4 that can be classified as a microtubule inhibitor. In this study, we evaluated the anti-hepatoma effect of COH-203 in vitro and in vivo and explored the underlying molecular mechanisms. COH-203 was shown to be more effective in inhibiting the proliferation of liver cancer cells compared with normal liver cells. COH-203 also displayed potent anti-tumor activity in a hepatocellular carcinoma xenograft model without significant toxicity. Mechanistic studies demonstrated that treatment with COH-203 induced mitotic arrest by inhibiting tubulin polymerization in BEL-7402 liver cancer cells. Long-term COH-203 treatment in BEL-7402 cells led to mitotic slippage followed by senescence via the p14{sup Arf}–p53–p21 and p16{sup INK4α}–Rb pathways. Furthermore, suppression of p53 via pifithrin-α (p53 inhibitor) and p53-siRNA attenuated COH-203-induced senescence in BEL-7402 cells, suggesting that COH-203 induced senescence p53-dependently. In conclusion, we report for the first time that COH-203, one compound in the combretastatin family, promotes anti-proliferative activity through the induction of p-53 dependent senescence. Our findings will provide a molecular rationale for the development of COH-203 as a promising anti-tumor agent.
ISSN 0006291X
Educational Use Research
Learning Resource Type Article
Publisher Date 2014-12-12
Publisher Place United States
Journal Biochemical and Biophysical Research Communications
Volume Number 455
Issue Number 3-4


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