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

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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

Fingerprint

Antimitotic Agents
Quinolones
Apoptosis Inducing Factor
Human Activities
Hepatocellular Carcinoma
Tubulin
Caspases
Cell Death
Cyclin B1
Caspase Inhibitors
Cyclin-Dependent Kinases
G2 Phase
Hep G2 Cells
Colchicine
Liver Neoplasms
Growth
Cell Cycle Checkpoints
Fluorescence Microscopy
Microtubules
Polymerization

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

CHM-1, a novel synthetic quinolone with potent and selective antimitotic antitumor activity against human hepatocellular carcinoma in vitro and in vivo. / Wang, Shih Wei; Pan, Shiow Lin; Huang, Yu Chun; Guh, Jih Hwa; Chiang, Po Cheng; Huang, Der Yi; Kuo, Sheng Chu; Lee, Kuo Hsiung; Teng, Che Ming.

In: Molecular Cancer Therapeutics, Vol. 7, No. 2, 01.02.2008, p. 350-360.

Research output: Contribution to journalArticle

Wang, Shih Wei ; Pan, Shiow Lin ; Huang, Yu Chun ; Guh, Jih Hwa ; Chiang, Po Cheng ; Huang, Der Yi ; Kuo, Sheng Chu ; Lee, Kuo Hsiung ; Teng, Che Ming. / CHM-1, a novel synthetic quinolone with potent and selective antimitotic antitumor activity against human hepatocellular carcinoma in vitro and in vivo. In: Molecular Cancer Therapeutics. 2008 ; Vol. 7, No. 2. pp. 350-360.
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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.",
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AU - Wang, Shih Wei

AU - Pan, Shiow Lin

AU - Huang, Yu Chun

AU - Guh, Jih Hwa

AU - Chiang, Po Cheng

AU - Huang, Der Yi

AU - Kuo, Sheng Chu

AU - Lee, Kuo Hsiung

AU - Teng, Che Ming

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