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

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 inductionmore » of p-53 dependent senescence. Our findings will provide a molecular rationale for the development of COH-203 as a promising anti-tumor agent.« less

Authors:
; ; ; ;  [1]; ;  [2];  [2];  [1]
  1. Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang (China)
  2. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang (China)
Publication Date:
OSTI Identifier:
22458454
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 455; Journal Issue: 3-4; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; COMPARATIVE EVALUATIONS; HEPATOMAS; IN VITRO; IN VIVO; LIVER; LIVER CELLS; MICROTUBULES; POLYMERIZATION; TOXICITY

Citation Formats

Qi, Huan, Zuo, Dai-Ying, Bai, Zhao-Shi, Xu, Jing-Wen, Li, Zeng-Qiang, Shen, Qi-Rong, Wang, Zhi-Wei, Zhang, Wei-Ge, E-mail: zhangweige2000@sina.com, and Wu, Ying-Liang, E-mail: yingliang_1016@163.com. COH-203, a novel microtubule inhibitor, exhibits potent anti-tumor activity via p53-dependent senescence in hepatocellular carcinoma. United States: N. p., 2014. Web. doi:10.1016/J.BBRC.2014.11.001.
Qi, Huan, Zuo, Dai-Ying, Bai, Zhao-Shi, Xu, Jing-Wen, Li, Zeng-Qiang, Shen, Qi-Rong, Wang, Zhi-Wei, Zhang, Wei-Ge, E-mail: zhangweige2000@sina.com, & Wu, Ying-Liang, E-mail: yingliang_1016@163.com. COH-203, a novel microtubule inhibitor, exhibits potent anti-tumor activity via p53-dependent senescence in hepatocellular carcinoma. United States. doi:10.1016/J.BBRC.2014.11.001.
Qi, Huan, Zuo, Dai-Ying, Bai, Zhao-Shi, Xu, Jing-Wen, Li, Zeng-Qiang, Shen, Qi-Rong, Wang, Zhi-Wei, Zhang, Wei-Ge, E-mail: zhangweige2000@sina.com, and Wu, Ying-Liang, E-mail: yingliang_1016@163.com. Fri . "COH-203, a novel microtubule inhibitor, exhibits potent anti-tumor activity via p53-dependent senescence in hepatocellular carcinoma". United States. doi:10.1016/J.BBRC.2014.11.001.
@article{osti_22458454,
title = {COH-203, a novel microtubule inhibitor, exhibits potent anti-tumor activity via p53-dependent senescence in hepatocellular carcinoma},
author = {Qi, Huan and Zuo, Dai-Ying and Bai, Zhao-Shi and Xu, Jing-Wen and Li, Zeng-Qiang and Shen, Qi-Rong and Wang, Zhi-Wei and Zhang, Wei-Ge, E-mail: zhangweige2000@sina.com and Wu, Ying-Liang, E-mail: yingliang_1016@163.com},
abstractNote = {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.},
doi = {10.1016/J.BBRC.2014.11.001},
journal = {Biochemical and Biophysical Research Communications},
number = 3-4,
volume = 455,
place = {United States},
year = {Fri Dec 12 00:00:00 EST 2014},
month = {Fri Dec 12 00:00:00 EST 2014}
}
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