GPX4 Inhibition Enhances the Antitumor Effect of PARP Inhibitor on Homologous Recombination Proficient Ovarian Cancer Cells.

IF 2.3 4区医学 Q3 ONCOLOGY

Current cancer drug targets Pub Date : 2024-08-26 DOI:10.2174/0115680096334278240821100404

Jiaxin Gu, Senmi Qian, Fangfang Qian, Xiaodong Wu, Lifeng Chen, Xiaojing Chen, Zhuoye Chen, Feifei Song, Mengxia Zheng, Lingfang Wang, Xiaodong Cheng

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引用次数: 0

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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抑制 GPX4 可增强 PARP 抑制剂对具有同源重组能力的卵巢癌细胞的抗肿瘤作用

背景：聚（ADP-核糖）聚合酶抑制剂（PARPi）目前广泛用于 BRCA1/2 基因突变或同源重组（HR）缺陷的卵巢癌，但对 HR 阳性患者的疗效有限。GPX4 是铁变态反应的关键调节因子，已被证实与多种药物敏感性有关。作为一种调节多种药物敏感性的分子，GPX4与PARPi在HR缺陷卵巢癌中的疗效之间的关系尚未阐明：本研究采用siRNA转染来调控GPX4的表达。方法：本研究采用 siRNA 转染法调控 GPX4 的表达，通过 CCK-8 检测法和流式细胞术确定 GPX4 抑制对 HR 阳性卵巢癌的影响。免疫荧光和彗星试验用于反映 DNA 损伤情况。使用 DCFH-DA 和流式细胞术测量 ROS 的产生。根据 Chou-Talalay 方法，使用 CompuSyn 软件计算 PARP 抑制剂和 RSL3 的组合指数：结果：GPX4抑制可使卵巢癌细胞对PARPi敏感，这是由于ROS生成和DNA双链断裂引起的氧化应激所致。将奥拉帕利（olaparib）和尼拉帕利（niraparib）与 GPX4 抑制剂 RSL3 结合使用也会产生协同效应：结论：将 GPX4 抑制剂与 PARP 抑制剂结合使用，可显著增加 DNA 损伤，最终导致具有熟练 HR 通路的癌细胞死亡。我们的研究结果可能会为HR功能良好的患者提供新的治疗方案，使他们从PARP抑制剂中获益并改善预后。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Current cancer drug targets 医学-肿瘤学

CiteScore

5.40

自引率

0.00%

发文量

105

审稿时长

1 months

期刊介绍： Current Cancer Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular drug targets involved in cancer, e.g. disease specific proteins, receptors, enzymes and genes. Current Cancer Drug Targets publishes original research articles, letters, reviews / mini-reviews, drug clinical trial studies and guest edited thematic issues written by leaders in the field covering a range of current topics on drug targets involved in cancer. As the discovery, identification, characterization and validation of novel human drug targets for anti-cancer drug discovery continues to grow; this journal has become essential reading for all pharmaceutical scientists involved in drug discovery and development.