https://scholars.lib.ntu.edu.tw/handle/123456789/564842
Title: | CHM-1, a novel synthetic quinolone with potent and selective antimitotic antitumor activity against human hepatocellular carcinoma in vitro and in vivo | Authors: | Wang S.-W. Pan S.-L. Huang Y.-C. JIH-HWA GUH Chiang P.-C. Huang D.-Y. Kuo S.-C. Lee K.-H. Teng C.-M. |
Issue Date: | 2008 | Journal Volume: | 7 | Journal Issue: | 2 | Start page/Pages: | 350-360 | Source: | Molecular Cancer Therapeutics | 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. Copyright ? 2008 American Association for Cancer Research. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-39749168393&doi=10.1158%2f1535-7163.MCT-07-2000&partnerID=40&md5=4b98891a3c1dd02e5694badee3b9f617 https://scholars.lib.ntu.edu.tw/handle/123456789/564842 |
ISSN: | 15357163 | DOI: | 10.1158/1535-7163.MCT-07-2000 | SDG/Keyword: | 2' fluoro 6,7 methylenedioxy 2 phenyl 4 quinolone; antibody; antimitotic agent; antineoplastic agent; apoptosis inducing factor; benzyloxycarbonylvalylalanylaspartyl fluoromethyl ketone; colchicine; cyclin B1; cyclin dependent kinase 1; cyclin dependent kinase inhibitor; doxorubicin; MPM2 antibody; paclitaxel; quinolone derivative; roscovitine; small interfering RNA; tubulin; unclassified drug; vincristine; animal experiment; animal model; antineoplastic activity; apoptosis; article; binding site; cancer cell; cancer inhibition; cell cycle arrest; cell cycle G2 phase; cell cycle M phase; cell death; cell line; cell viability; concentration response; controlled study; drug potentiation; enzyme activation; gene targeting; growth inhibition; human; human cell; IC 50; immunofluorescence test; in vitro study; in vivo study; inoculation; lifespan; liver cell carcinoma; male; microscopy; microtubule assembly; microtubule organizing center; mitochondrion; mouse; nonhuman; priority journal; tumor growth; Animals; Antineoplastic Agents; Apoptosis; Apoptosis Inducing Factor; Carcinoma, Hepatocellular; Caspases; Cell Division; Cell Proliferation; Dioxoles; G2 Phase; Humans; Liver Neoplasms; Male; Mice; Mice, SCID; Microtubules; Models, Biological; Quinolones; Substrate Specificity; Tumor Cells, Cultured; Xenograft Model Antitumor Assays [SDGs]SDG3 |
Appears in Collections: | 藥學系 |
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