Abstract
Hepatocellular carcinoma (HCC) is one of the most deadly human cancers. Chronic hepatitis B virus (HBV) infection is one of the predominant risk factors associated with the development of HCC and complicates the treatment of HCC. In this study, we demonstrate that a HBV-positive HCC cell line HepG2.2.15, was more resistant to chemotherapy agents than its parental HBV-negative cell line HepG2. HBV-positive HCC cells exhibited defective Chk1 phosphorylation and increased chromosomal instability. CGK733, a small molecule inhibitor reportedly targeting the kinase activities of ATM and ATR, significantly enhanced taxol-induced cytotoxicity in HBV-positive HepG2.2.15 cells. The mechanism lies in CGK733 triggers the formation of multinucleated cells thus promotes the premature mitotic exit of taxol-induced mitotic-damaged cells through multinucleation and mitotic catastrophe in HBV-positive HepG2.2.15 cells. These results suggest that CGK733 could potentially reverse the taxol resistance in HBV-positive HCC cells and may suggest a novel strategy to treat HBV-infected HCC patients.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents, Phytogenic / therapeutic use*
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Antineoplastic Combined Chemotherapy Protocols*
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Ataxia Telangiectasia Mutated Proteins
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Benzeneacetamides / therapeutic use*
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / virology
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Cell Cycle Proteins / antagonists & inhibitors
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Checkpoint Kinase 1
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DNA-Binding Proteins / antagonists & inhibitors
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Drug Resistance, Neoplasm / drug effects*
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Giant Cells / drug effects
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Hep G2 Cells
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Hepatitis B virus / isolation & purification
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Humans
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Liver Neoplasms / drug therapy*
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Liver Neoplasms / virology
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Paclitaxel / therapeutic use*
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Phosphorylation
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Protein Kinase Inhibitors / therapeutic use*
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Protein Kinases / genetics
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Thiourea / analogs & derivatives*
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Thiourea / therapeutic use
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Tumor Suppressor Proteins / antagonists & inhibitors
Substances
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Antineoplastic Agents, Phytogenic
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Benzeneacetamides
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CGK 733
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Cell Cycle Proteins
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DNA-Binding Proteins
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Protein Kinase Inhibitors
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Tumor Suppressor Proteins
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Protein Kinases
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ATM protein, human
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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CHEK1 protein, human
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Checkpoint Kinase 1
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Protein Serine-Threonine Kinases
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Thiourea
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Paclitaxel