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Research Articles: Therapeutics, Targets, and Development

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

¹ Pharmacological Institute and ² School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; ³ Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan; and ⁴ Natural Products Laboratory, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina

Requests for reprints: Che-Ming Teng, Pharmacological Institute, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei, Taiwan. Phone: 886-2-2322-1742; Fax: 886-2-2322-1742. E-mail: cmteng{at}ntu.edu.tw

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. [Mol Cancer Ther 2008;7(2):350–60]

Grant support: National Science Council of the Republic of China grant NSC 92-2320-B-002-072 (C-M. Teng) and NIH grant CA17625 (K-H. Lee).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 8/26/07; revised 10/26/07; accepted 11/ 9/07.