title: COH-203, a novel microtubule inhibitor, exhibits potent anti-tumor activity via p53-dependent senescence in hepatocellular carcinoma.
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(Arf)-p53-p21 and p16(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.
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Qi
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Dai-Ying
authors.initials: DY
authors.lastname: Zuo
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Zhao-Shi
authors.initials: ZS
authors.lastname: Bai
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Jing-Wen
authors.initials: JW
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Zeng-Qiang
authors.initials: ZQ
authors.lastname: Li
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Qi-Rong
authors.initials: QR
authors.lastname: Shen
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Wang
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China. Electronic address: zhangweige2000@sina.com.
authors.forename: Wei-Ge
authors.initials: WG
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China. Electronic address: yingliang_1016@163.com.
authors.forename: Ying-Liang
authors.initials: YL
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D016922:Cellular Senescence; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000187:drug effects; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008870:Microtubules / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C000595080:5-(3-hydroxy-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-3H-1,2-dithiol-3-one; D000970:Antineoplastic Agents; D006573:Heterocyclic Compounds, 1-Ring; D034741:RNA, Small Interfering; D013267:Stilbenes; C495901:TP53 protein, human; D014404:Tubulin; D050257:Tubulin Modulators; D016159:Tumor Suppressor Protein p53; C058728:fosbretabulin
keywords: COH-203; Hepatocellular carcinoma; Microtubules; Senescence; p53