Gu Jiaxin, Qian Senmi, Qian Fangfang, Wu Xiaodong, Chen Lifeng, Chen Xiaojing, Chen Zhuoye, Song Feifei, Zheng Mengxia, Wang Lingfang, Cheng Xiaodong
Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Zhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Hangzhou, Zhejiang, China.
Curr Cancer Drug Targets. 2024 Aug 26. doi: 10.2174/0115680096334278240821100404.
Poly (ADP-ribose) polymerase inhibitors (PARPi) are now widely used in BRCA1/2 mutation or homologous recombination (HR) deficiency ovarian cancer but have limited efficacy in HR-proficient patients. GPX4 is a key regulator of ferroptosis and has been proven to be associated with multiple drug sensitivities. As a molecule that regulates the sensitivity of multiple drugs, the relationship between GPX4 and the efficacy of PARPi in HR-proficient ovarian cancer has not been elucidated.
In this study, siRNA transfection was used to regulate the expression of GPX4. The effect of GPX4 inhibition on HR-proficient ovarian cancer was determined by CCK-8 assay and flow cytometry. Immunofluorescence and comet assays were used to reflect DNA dam-age. ROS production was measured using DCFH-DA and flow cytometry. The combination index of PARP inhibitors and RSL3 was calculated using CompuSyn software based on Chou-Talalay methodology.
GPX4 inhibition confers HR-proficient ovarian cancer cells sensitive to PARPi due to ROS generation and oxidative stress caused by DNA double-strand breakage. The combina-tion of olaparib and niraparib with GPX4 inhibitor RSL3 also showed a synergistic effect.
Combining GPX4 inhibition with PARP inhibitors resulted in a notable increase in DNA damage, ultimately causing the death of cancer cells with proficient HR pathways. Our findings may provide new therapeutic options for HR-proficient patients to benefit from PARP inhibitors and improve outcomes.
聚（ADP - 核糖）聚合酶抑制剂（PARPi）目前广泛应用于BRCA1/2突变或同源重组（HR）缺陷的卵巢癌，但在HR功能正常的患者中疗效有限。GPX4是铁死亡的关键调节因子，已被证明与多种药物敏感性相关。作为一种调节多种药物敏感性的分子，GPX4与PARPi在HR功能正常的卵巢癌中的疗效之间的关系尚未阐明。
在本研究中，使用小干扰RNA（siRNA）转染来调节GPX4的表达。通过CCK - 8测定法和流式细胞术确定GPX4抑制对HR功能正常的卵巢癌的影响。免疫荧光和彗星试验用于反映DNA损伤。使用DCFH - DA和流式细胞术测量活性氧（ROS）的产生。基于Chou - Talalay方法，使用CompuSyn软件计算PARP抑制剂和RSL3的联合指数。
由于DNA双链断裂导致的ROS生成和氧化应激，GPX4抑制使HR功能正常的卵巢癌细胞对PARPi敏感。奥拉帕利和尼拉帕利与GPX4抑制剂RSL3联合使用也显示出协同作用。
将GPX4抑制与PARP抑制剂联合使用可显著增加DNA损伤，最终导致HR通路功能正常的癌细胞死亡。我们的研究结果可能为HR功能正常的患者提供新的治疗选择，使其从PARP抑制剂中获益并改善预后。
