CHM-1, a novel synthetic quinolone with potent and selective antimitotic antitumor activity against human hepatocellular carcinoma in vitro and in vivo.
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 IC(50) 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 G(2)-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.
Wang
Shih-Wei
SW
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
Pan
Shiow-Lin
SL
Huang
Yu-Chun
YC
Guh
Jih-Hwa
JH
Chiang
Po-Cheng
PC
Huang
Der-Yi
DY
Kuo
Sheng-Chu
SC
Lee
Kuo-Hsiung
KH
Teng
Che-Ming
CM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology* / Q000627:therapeutic use*; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D015363:Quinolones / Q000494:pharmacology* / Q000627:therapeutic use*; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C525063:2'-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone; D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; D004149:Dioxoles; D015363:Quinolones; D020169:Caspases