The overexpression of ABC transporters on cancer cell membranes is one of the most common causes of multidrug resistance (MDR). This study investigates the impact of ABCC1 and ABCG2 on the resistance to talazoparib (BMN-673), a potent poly (ADP-ribose) polymerase (PARP) inhibitor, in ovarian cancer treatment. The cell viability test was used to indicate the effect of talazoparib in different cell lines. Computational molecular docking analysis was conducted to simulate the interaction between talazoparib and ABCC1 or ABCG2. The mechanism of talazoparib resistance was investigated by constructing talazoparib-resistant subline A2780/T4 from A2780 through drug selection with gradually increasing talazoparib concentration. Talazoparib cytotoxicity decreased in drug-selected or gene-transfected cell lines overexpressing ABCC1 or ABCG2 but can be restored by ABCC1 or ABCG2 inhibitors. Talazoparib competitively inhibited substrate drug efflux activity of ABCC1 or ABCG2. Upregulated ABCC1 and ABCG2 protein expression on the plasma membrane of A2780/T4 cells enhances resistance to other substrate drugs, which could be overcome by the knockout of either gene. In vivo experiments confirmed the retention of drug-resistant characteristics in tumor xenograft mouse models. The therapeutic efficacy of talazoparib in cancer may be compromised by its susceptibility to MDR, which is attributed to its interactions with the ABCC1 or ABCG2 transporters. The overexpression of these transporters can potentially diminish the therapeutic impact of talazoparib in cancer treatment.

中文翻译：

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ABCC1 和 ABCG2 的过度表达导致对多聚（ADP-核糖）聚合酶抑制剂他佐帕尼的耐药性

癌细胞膜上 ABC 转运蛋白的过度表达是多药耐药性 (MDR) 的最常见原因之一。本研究探讨了在卵巢癌治疗中 ABCC1 和 ABCG2 对 Talazoparib (BMN-673) 耐药性的影响，talazoparib (BMN-673) 是一种有效的多聚 (ADP-核糖) 聚合酶 (PARP) 抑制剂。细胞活力测试用于表明他拉佐帕尼在不同细胞系中的作用。进行计算分子对接分析来模拟他拉佐帕尼与 ABCC1 或 ABCG2 之间的相互作用。通过逐渐增加talazoparib浓度的药物选择，从A2780构建talazoparib耐药亚系A2780/T4，研究talazoparib耐药机制。Talazoparib 在药物选择或基因转染的过表达 ABCC1 或 ABCG2 的细胞系中细胞毒性降低，但可以通过 ABCC1 或 ABCG2 抑制剂恢复。Talazoparib 竞争性抑制 ABCC1 或 ABCG2 的底物药物流出活性。A2780/T4细胞质膜上ABCC1和ABCG2蛋白表达上调可增强对其他底物药物的耐药性，这可以通过敲除任一基因来克服。体内实验证实了肿瘤异种移植小鼠模型中保留了耐药特征。他拉佐帕尼在癌症中的治疗效果可能会因其对 MDR 的敏感性而受到影响，这归因于它与 ABCC1 或 ABCG2 转运蛋白的相互作用。这些转运蛋白的过度表达可能会削弱他拉佐帕尼在癌症治疗中的治疗作用。