title: 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.affiliation: Department of Microbiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.forename: Bin
authors.initials: B
authors.lastname: Zuo
authors.forename: Haibin
authors.initials: H
authors.lastname: Wang
authors.forename: Laifeng
authors.initials: L
authors.lastname: Ren
authors.forename: Peng
authors.initials: P
authors.lastname: Yang
authors.forename: Ming
authors.initials: M
authors.lastname: Zeng
authors.forename: Dan
authors.initials: D
authors.lastname: Duan
authors.forename: Cong
authors.initials: C
authors.lastname: Liu
authors.forename: Mingyuan
authors.initials: M
authors.lastname: Li
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D064007:Ataxia Telangiectasia Mutated Proteins; D044482:Benzeneacetamides / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000821:virology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D000071877:Checkpoint Kinase 1; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015726:Giant Cells / Q000187:drug effects; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000302:isolation & purification; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000821:virology; D017239:Paclitaxel / Q000627:therapeutic use*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011494:Protein Kinases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D013890:Thiourea / Q000031:analogs & derivatives* / Q000627:therapeutic use; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D044482:Benzeneacetamides; C512273:CGK 733; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047428:Protein Kinase Inhibitors; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; D013890:Thiourea; D017239:Paclitaxel