据报道，PARP抑制剂联合抗血管生成药物可改善BRCA野生型卵巢癌患者的预后，但联合用药的机制尚不清楚。本研究探讨阿帕替尼联合奥拉帕尼治疗卵巢癌的机制。
方法本研究以人卵巢癌细胞株A2780和OVCAR3为实验对象,采用Western blot检测阿帕替尼和奥拉帕尼处理后铁死亡相关蛋白GPX4的表达量。利用SuperPred数据库预测阿帕替尼和奥拉帕尼联合作用的靶点，并通过Western blot实验验证预测结果，探讨阿帕替尼和奥拉帕尼诱导铁死亡的机制。
结果阿帕替尼联合奥拉帕尼诱导 p53 野生型细胞铁死亡，p53 突变细胞产生耐药性。p53 激活剂 RITA 使耐药细胞对阿帕替尼联合奥拉帕尼诱导的铁死亡敏感。阿帕替尼与奥拉帕尼通过 p53 依赖性方式联合治疗卵巢癌中诱导的铁死亡。进一步研究表明，阿帕替尼联合奥拉帕尼通过抑制Nrf2和自噬的表达，从而抑制GPX4的表达，诱导铁死亡。Nrf2 激活剂 RTA408 和自噬激活剂雷帕霉素可挽救联合药物诱导的铁死亡。
结论这一发现揭示了阿帕替尼联合奥拉帕尼诱导p53野生型卵巢癌细胞铁死亡的具体机制，为临床联合使用阿帕替尼和奥拉帕尼治疗p53野生型卵巢癌患者提供了理论依据。
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Apatinib combined with olaparib induces ferroptosis via a p53-dependent manner in ovarian cancerObjective
PARP inhibitors combined with antiangiogenic drugs have been reported to improve outcomes in BRCA wild-type ovarian cancer patients, the mechanism of the combination is unclear. In this study, we explored the mechanism of apatinib combined with olaparib in the treatment of ovarian cancer.
MethodsIn this study, human ovarian cancer cell lines A2780 and OVCAR3 were used as experimental objects, and the expression of ferroptosis-related protein GPX4 after treatment with apatinib and olaparib was detected by Western blot. The SuperPred database was used to predict the target of the combined action of apatinib and olaparib, and the predicted results were verified by Western blot experiment to explore the mechanism of ferroptosis induced by apatinib and olaparib.
ResultsApatinib combined with olaparib-induced ferroptosis in p53 wild-type cells, and p53 mutant cells developed drug resistance. The p53 activator RITA sensitized drug-resistant cells to ferroptosis induced by apatinib combined with olaparib. Apatinib combined with olaparib-induced ferroptosis via a p53-dependent manner in ovarian cancer. Further studies showed that apatinib combined with olaparib-induced ferroptosis by inhibiting the expression of Nrf2 and autophagy, thereby inhibiting the expression of GPX4. The Nrf2 activator RTA408 and the autophagy activator rapamycin rescued the combination drug-induced ferroptosis.
ConclusionThis discovery revealed the specific mechanism of ferroptosis induced by apatinib combined with olaparib in p53 wild-type ovarian cancer cells and provided a theoretical basis for the clinical combined use of apatinib and olaparib in p53 wild-type ovarian cancer patients.