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.
Keywords: 4-Amino-1,8-naphythalimide; Arsenic trioxide; Cyclin B1; G2/M phase checkpoint; PARP-1.
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