卵巢腺癌是预后最差、死亡率最高的妇科恶性肿瘤。在治疗的第一阶段，化疗是有效的，但长期使用和高剂量导致大多数患者出现治疗耐药和复发，这对临床医生来说是一个重大挑战。我们开发了 PEP-010，一种细胞穿透性促凋亡肽，可破坏 caspase-9 和蛋白磷酸酶 2A 之间的蛋白质-蛋白质相互作用，从而恢复它们在凋亡途径中的活性。 MTT 测定或膜联蛋白-V/碘化丙啶染色和流式细胞术分析用于评估卵巢癌细胞系中 PEP-010 单一疗法或与紫杉醇联合治疗后对化疗的敏感性和细胞凋亡。使用 γH2AX 标记通过免疫荧光评估 DNA 损伤。我们在此表明​​，PEP-010 在单一疗法中可有效诱导来自对不同化疗耐药的卵巢腺癌细胞模型中高达 55% 的细胞死亡。此外，当与复发性卵巢癌的治疗选择之一紫杉醇联合使用时，PEP-010显示出有益效果，导致紫杉醇的IC50降低2.2倍，并导致87%的细胞凋亡。上述结果表明 PEP-010 具有潜在的治疗意义，并导致选择卵巢腺癌作为正在进行的临床试验的主要适应症之一。版权所有 © 2024 Lacroix、Farhat、Robert、Brenner、Wiels 和 Germini。

Ovarian adenocarcinoma is the gynecological malignancy with the worst prognosis and the highest mortality rate. In the first stages of treatment, chemotherapy results effective, but its prolonged use and high doses lead to the appearance of resistance to treatments and relapse in most patients, representing a major challenge for clinicians. We developed PEP-010, a cell penetrating proapoptotic peptide disrupting the protein-protein interaction between caspase-9 and protein phosphatase 2A, thereby leading to the recovery of their activity in the apoptotic pathway. MTT assay or Annexin-V/Propidium Iodide staining and flow cytometry analysis were used to assess sensitivity to chemotherapies and apoptosis after treatment with PEP-010 in monotherapy or in combination with paclitaxel in ovarian carcinoma cell lines. DNA damage was assessed by immunofluorescence using γH2AX marker. We show here that PEP-010 effectively induces cell death in monotherapy on in up to 55% of cells from ovarian adenocarcinoma cell models resistant to different chemotherapies. Moreover, when used in combination with paclitaxel, one of the therapeutic options for recurrent ovarian carcinoma, PEP-010 showed a beneficial effect leading to the reduction of the IC50 of paclitaxel of 2.2 times and to apoptosis in 87% of cells. The described results suggest the potential therapeutic interest for PEP-010 and lead to the choice of ovarian adenocarcinoma as one of the major indications of the ongoing clinical trial.Copyright © 2024 Lacroix, Farhat, Robert, Brenner, Wiels and Germini.