CGK733 enhances multinucleated cell formation and cytotoxicity induced by taxol in Chk1-deficient HBV-positive hepatocellular carcinoma cells.

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.

• Authors: Huan Wang, Bin Zuo, Haibin Wang, Laifeng Ren, Peng Yang, Ming Zeng, Dan Duan, Cong Liu, Mingyuan Li
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 422 Issue 1 Pg. 103-8 (May 25 2012) ISSN: 1090-2104 [Electronic] United States
• PMID: 22564734 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Benzeneacetamides
• CGK 733
• Cell Cycle Proteins
• DNA-Binding Proteins
• Protein Kinase Inhibitors
• Tumor Suppressor Proteins
• Protein Kinases
• ATM protein, human
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins
• CHEK1 protein, human
• Checkpoint Kinase 1
• Protein Serine-Threonine Kinases
• Thiourea
• Paclitaxel

Topics

• Antineoplastic Agents, Phytogenic (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols
• Ataxia Telangiectasia Mutated Proteins
• Benzeneacetamides (therapeutic use)
• Carcinoma, Hepatocellular (drug therapy, virology)
• Cell Cycle Proteins (antagonists & inhibitors)
• Checkpoint Kinase 1
• DNA-Binding Proteins (antagonists & inhibitors)
• Drug Resistance, Neoplasm (drug effects)
• Giant Cells (drug effects)
• Hep G2 Cells
• Hepatitis B virus (isolation & purification)
• Humans
• Liver Neoplasms (drug therapy, virology)
• Paclitaxel (therapeutic use)
• Phosphorylation
• Protein Kinase Inhibitors (therapeutic use)
• Protein Kinases (genetics)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Thiourea (analogs & derivatives, therapeutic use)
• Tumor Suppressor Proteins (antagonists & inhibitors)