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

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• 作者：Huan Wang^a ; ^b ; ¹ ; Bin Zuo^a ; ^b ; ¹ ; Haibin Wang^b ; Laifeng Ren^a ; ^b ; Peng Yang^b ; Ming Zeng^b ; Dan Duan^b ; Cong Liu^b ; ^{lcmicro@yahoo.com} ; Mingyuan Li^a ; ^c ; ^{lmy3985@sina.com}
• 关键词：Hepatocellular carcinoma (HCC) ; Hepatitis B virus (HBV) ; Taxol ; CGK733
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2012
• 期刊代码：159_0006291x
• 类别：bio
• 出版时间：25 May, 2012
• 卷：422
• 期：1
• 页码：103-108
• 文件大小：858 K

摘要

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.