铂类化疗仍是卵巢癌（OC）的主要系统治疗方法。然而，铂类和聚（腺苷二磷酸核糖）聚合酶抑制剂（PARPi）耐药的不可避免发展与不良疗效相关，成为治疗该疾病的主要障碍。本研究开发了“一体化”纳米粒子，包含PARPi奥拉帕尼布和镓（Ga）（III）（奥拉帕尼布-镓）以有效逆转铂类耐药A2780-cis和SKOV3-cis OC细胞以及SKOV3-cis肿瘤模型中的PARPi耐药性。值得注意的是，奥拉帕尼布-镓抑制SKOV3-cis肿瘤生长，毒性微不足道。此外，与氟环唑、卡铂治疗对比，奥拉帕尼布-镓与顺铂或卡铂联用治疗的A2780-cis和SKOV3-cis细胞中，抑制效果更为明显。机制上，联合治疗诱导DNA损伤，激活失调性毛细血管扩张症、自修复能力受损－Rad3类蛋白激酶（ATR）检查点激酶1（Chk1）/Chk2信号转导通路。这导致细胞周期停留在S和G2/M期，最终由于不可修复的DNA损伤而引起凋亡和细胞死亡。此外，在SKOV3-cis肿瘤携带的动物模型中，奥拉帕尼布-镓和顺铂或卡铂联合治疗取得了有效的治疗反应。总之，本研究结果表明，奥拉帕尼布-镓在铂类耐药性OC细胞中具有治疗意义，而奥拉帕尼布-镓与顺铂或卡铂联用治疗可能是治疗同时展现PARPi和铂类耐药的OC患者的有前途的方法。版权所有©2023年杨洋等。

Platinum-based chemotherapy remains the main systemic treatment of ovarian cancer (OC). However, the inevitable development of platinum and poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) resistance is associated with poor outcomes, which becomes a major obstacle in the management of this disease. The present study developed "all-in-one" nanoparticles that contained the PARPi olaparib and gallium (Ga) (III) (olaparib-Ga) to effectively reverse PARPi resistance in platinum-resistant A2780-cis and SKOV3-cis OC cells and in SKOV3-cis tumor models. Notably, the olaparib-Ga suppressed SKOV3-cis tumor growth with negligible toxicity. Moreover, the suppression effect was more evident when combining olaparib-Ga with cisplatin or carboplatin, as evaluated in A2780-cis and SKOV3-cis cells. Mechanistically, the combined treatment induced DNA damage, which elicited the activation of ataxia telangiectasia mutated (ATM)/AMT- and Rad3-related (ATR) checkpoint kinase 1 (Chk1)/Chk2 signal transduction pathways. This led to the arrest of cell cycle progression at S and G2/M phases, which eventually resulted in apoptosis and cell death due to unrepairable DNA damage. In addition, effective therapeutic responses to olaparib-Ga and cisplatin combination or olaparib-Ga and carboplatin combination were observed in SKOV3-cis tumor-bearing animal models. Altogether, the present findings demonstrate that olaparib-Ga has therapeutic implications in platinum-resistant OC cells, and the combination of olaparib-Ga with cisplatin or carboplatin may be promising for treating patients with OC who exhibit resistance to both PARPi and platinum.Copyright © 2023 Yangyang Li et al.