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

Biochem Biophys Res Commun. 2014 Dec 12;455(3-4):262-8. doi: 10.1016/j.bbrc.2014.11.001. Epub 2014 Nov 6.

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.

Keywords: COH-203; Hepatocellular carcinoma; Microtubules; Senescence; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Hepatocellular / drug therapy*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Cellular Senescence
  • Heterocyclic Compounds, 1-Ring / chemistry
  • Heterocyclic Compounds, 1-Ring / pharmacology*
  • Humans
  • Liver / drug effects
  • Liver Neoplasms / drug therapy*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Microtubules / drug effects
  • RNA, Small Interfering / metabolism
  • Stilbenes / chemistry
  • Stilbenes / pharmacology*
  • Tubulin / chemistry
  • Tubulin Modulators / chemistry
  • Tumor Suppressor Protein p53 / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • 5-(3-hydroxy-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-3H-1,2-dithiol-3-one
  • Antineoplastic Agents
  • Heterocyclic Compounds, 1-Ring
  • RNA, Small Interfering
  • Stilbenes
  • TP53 protein, human
  • Tubulin
  • Tubulin Modulators
  • Tumor Suppressor Protein p53
  • fosbretabulin