CHM-1, a novel synthetic quinolone with potent and selective antimitotic antitumor activity against human hepatocellular carcinoma in vitro and in vivo

Shih Wei Wang, Shiow Lin Pan, Yu Chun Huang, Jih Hwa Guh, Po Cheng Chiang, Der Yi Huang, Sheng Chu Kuo, Kuo Hsiung Lee, Che Ming Teng

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Hepatocellular carcinoma is highly chemoresistant to currently available chemotherapeutic agents. In this study, 2′-fluoro-6,7-methylenedioxy-2- phenyl-4-quinolone (CHM-1), a synthetic 6,7-substituted 2-phenyl-4-quinolone, was identified as a potent and selective antitumor agent in human hepatocellular carcinoma. CHM-1 induced growth inhibition of HA22T, Hep3B, and HepG2 cells in a concentration-dependent manner but did not obviously impair the viability of normal cells at the IC50 for liver cancer cells. CHM-1-induced apoptosis was also characterized by immunofluorescence microscopy. CHM-1 interacted with tubulin at the colchicine-binding site, markedly inhibited tubulin polymerization both in vitro and in vivo, and disrupted microtubule organization. CHM-1 caused cell cycle arrest at G2-M phase by activating Cdc2/cyclin B1 complex activity. CHM-1-induced cell death, activation of Cdc2 kinase activity, and elevation of MPM2 phosphoepitopes were profoundly attenuated by roscovitine, a specific cyclin-dependent kinase inhibitor. CHM-1 did not modulate the caspase cascade, and the pan-caspase-inhibitor z-VAD-fmk did not abolish CHM-1-induced cell death. However, CHM-1 induced the translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus. Small interfering RNA targeting of AIF substantially attenuated CHM-1-induced AIF translocation. Importantly, CHM-1 inhibited tumor growth and prolonged the lifespan in mice inoculated with HA22T cells. In conclusion, we show that CHM-1 exhibits a novel antimitotic antitumor activity against human hepatocellular carcinoma both in vitro and in vivo via a caspase-independent pathway. CHM-1 is a promising chemotherapeutic agent worthy of further development into a clinical trial candidate for treating cancer, especially hepatocellular carcinoma.

Original languageEnglish
Pages (from-to)350-360
Number of pages11
JournalMolecular Cancer Therapeutics
Volume7
Issue number2
DOIs
Publication statusPublished - Feb 1 2008
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

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