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

A37 Hepatocellular carcinoma (HCC) is highly chemoresistant to currently available chemotherapeutic agents. In the present study, CHM-1, a synthetic 29-fluoro-6,7- methylenedioxy-2-phenyl-4-quinolone, was identified as a potent and selective antitumor agent in human HCC. CHM-1 induced growth inhibition and apoptosis in HA22T, Hep3B, and HepG2 cells, but did not obviously impair the viability of normal cells at the IC 50 for liver cancer cells. CHM-1 interacted with tubulin at the colchicine-binding site, markedly inhibited tubulin polymerization both in vitro and in vivo . 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, and elevation of MPM2 phosphoepitopes were profoundly attenuated by roscovitine. 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 effectively protected HA22T and Hep3B cells against CHM-1-induced cell death. Importantly, CHM-1 inhibited tumor growth and prolonged the life span in mice inoculated with HA22T cells. Taken together, we conclude that CHM-1 exhibits a novel antimitotic antitumor activity against human HCC cells both in vitro and in vivo via a caspase-independent pathway. Thus, CHM-1 is a promising chemotherapeutic agent worthy of further development into a clinical trial candidate for treating cancer, especially HCC.