title: PARP-1 inhibitor sensitizes arsenic trioxide in hepatocellular carcinoma cells via abrogation of G2/M checkpoint and suppression of DNA damage repair.
abstract: Arsenic trioxide (ATO) is successfully used to treat hematological malignancies. However, the clinical application of the agent in solid tumors is largely limited by its dose-dependent toxicity which results from the high intrinsic resistance of the cancer cells. In this study, we firstly identified a series of sensitization effects of 4AN, a PARP-1 inhibitor, on human hepatocellular carcinoma cell line HepG2 to ATO treatment. We showed that treatment of HepG2 cells with 4AN promoted ATO-induced cell death in a synergistic manner. The ATO-sensitization by 4AN was associated with its effect on abrogation of ATO-induced G2/M checkpoint which impairs DNA damage repair and promotes cell apoptosis. Further analysis demonstrated that the ATO-induced G2/M checkpoint was closely related to a decrease in cyclin B1, a key G2/M mediator; whereas 4AN up-regulated the expression of cyclin B1 in ATO-treated cells, which may be at least partly responsible for its effect on abrogation of ATO-induced G2/M checkpoint. This was further supported by the result showing that down-regulation of cyclin B1 using siRNA could restore the G2/M checkpoint in cells co-treated with ATO and 4AN, thereby improving DNA damage repair and decreasing apoptosis. Our study indicates that the abrogation of G2/M checkpoint and the suppression of DNA damage repair contribute to ATO-sensitization by PARP-1 inhibitor in HepG2 cells, which provides a novel insight into the chemo-sensitization mechanism of PARP-1 inhibitor.
authors.affiliation: Department of Environmental Health, West China School of Public Health, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Qingying
authors.initials: Q
authors.lastname: Luo
authors.affiliation: Department of Environmental Health, West China School of Public Health, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Laboratory, Mianyang 404 Hospital, Mianyang, Sichuan, People's Republic of China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Environmental Health, West China School of Public Health, Sichuan University, Chengdu, Sichuan, People's Republic of China. Electronic address: zhangzunzhen@163.com.
authors.forename: Zunzhen
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D015057:1-Naphthylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D053644:Naphthalimides / Q000494:pharmacology*; D010087:Oxides / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015363:Quinolones / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D056744:Cyclin B1; D004791:Enzyme Inhibitors; D053644:Naphthalimides; D010087:Oxides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015363:Quinolones; C086538:4-amino-1,8-naphthalimide; D015057:1-Naphthylamine; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D000077237:Arsenic Trioxide
keywords: 4-Amino-1,8-naphythalimide; Arsenic trioxide; Cyclin B1; G2/M phase checkpoint; PARP-1