COH-203, a novel microtubule inhibitor, exhibits potent anti-tumor activity via p53-dependent senescence in hepatocellular carcinoma

• Published in: Biochemical and biophysical research communications Vol. 455; no. 3-4; pp. 262 - 268
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.12.2014
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Carcinoma, Hepatocellular - drug therapy; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cellular Senescence; COH-203; COMPARATIVE EVALUATIONS; Hepatocellular carcinoma; HEPATOMAS; Heterocyclic Compounds, 1-Ring - chemistry; Heterocyclic Compounds, 1-Ring - pharmacology; Humans; IN VITRO; IN VIVO; LIVER; Liver - drug effects; LIVER CELLS; Liver Neoplasms - drug therapy; Male; Mice; Mice, Inbred BALB C; MICROTUBULES; Microtubules - drug effects; p53; POLYMERIZATION; RNA, Small Interfering - metabolism; Senescence; Stilbenes - chemistry; Stilbenes - pharmacology; TOXICITY; Tubulin - chemistry; Tubulin Modulators - chemistry; Tumor Suppressor Protein p53 - metabolism; Xenograft Model Antitumor Assays; COH-203; Hepatocellular carcinoma; Senescence; Microtubules; p53
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2014.11.001

[Display omitted] •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. 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 p14Arf–p53–p21 and p16INK4α–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.