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聚腺苷二磷酸核糖聚合酶-1 抑制剂通过消除 G2/M 检查点和抑制 DNA 损伤修复使三氧化二砷在肝癌细胞中敏感化。

PARP-1 inhibitor sensitizes arsenic trioxide in hepatocellular carcinoma cells via abrogation of G2/M checkpoint and suppression of DNA damage repair.

机构信息

Department of Environmental Health, West China School of Public Health, Sichuan University, Chengdu, Sichuan, People's Republic of China.

Department of Laboratory, Mianyang 404 Hospital, Mianyang, Sichuan, People's Republic of China.

出版信息

Chem Biol Interact. 2015 Jan 25;226:12-22. doi: 10.1016/j.cbi.2014.12.007. Epub 2014 Dec 11.

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.

摘要

三氧化二砷(ATO)成功地用于治疗血液系统恶性肿瘤。然而,该药物在实体瘤中的临床应用在很大程度上受到其剂量依赖性毒性的限制,这是由于癌细胞的固有高耐药性所致。在这项研究中,我们首先确定了 PARP-1 抑制剂 4AN 对人肝癌细胞系 HepG2 对 ATO 治疗的一系列增敏作用。我们表明,用 4AN 处理 HepG2 细胞以协同方式促进 ATO 诱导的细胞死亡。4AN 通过 ATO 增敏与阻断 ATO 诱导的 G2/M 检查点有关,该检查点损害 DNA 损伤修复并促进细胞凋亡。进一步的分析表明,ATO 诱导的 G2/M 检查点与细胞周期蛋白 B1 的减少密切相关,细胞周期蛋白 B1 是 G2/M 调节的关键介质;而 4AN 上调 ATO 处理细胞中 cyclin B1 的表达,这可能至少部分是其对阻断 ATO 诱导的 G2/M 检查点的作用的原因。这一结果进一步得到了支持,表明使用 siRNA 下调 cyclin B1 可以恢复 ATO 和 4AN 共同处理的细胞中的 G2/M 检查点,从而改善 DNA 损伤修复并减少细胞凋亡。我们的研究表明,G2/M 检查点的阻断和 DNA 损伤修复的抑制有助于 PARP-1 抑制剂在 HepG2 细胞中的增敏作用,这为 PARP-1 抑制剂的化疗增敏机制提供了新的见解。

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