Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, 7624 Pécs, Hungary.
Szentagothai Research Centre, University of Pécs, 7624 Pécs, Hungary.
Int J Mol Sci. 2021 Feb 19;22(4):2056. doi: 10.3390/ijms22042056.
Triple-negative breast cancer (TNBC) has a poor prognosis as the therapy has several limitations, most importantly, treatment resistance. In this study we examined the different responses of triple-negative breast cancer line MDA-MB-231 and hormone receptor-positive breast cancer line MCF7 to a combined treatment including olaparib, a poly-(ADP ribose) polymerase (PARP) inhibitor, oxaliplatin, a third-generation platinum compound and LY294002, an Akt pathway inhibitor. We applied the drugs in a single, therapeutically relevant concentration individually and in all possible combinations, and we assessed the viability, type of cell death, reactive oxygen species production, cell-cycle phases, colony formation and invasive growth. In agreement with the literature, the MDA-MB-231 cells were more treatment resistant than the MCF7 cells. However, and in contrast with the findings of others, we detected no synergistic effect between olaparib and oxaliplatin, and we found that the Akt pathway inhibitor augmented the cytostatic properties of the platinum compound and/or prevented the cytoprotective effects of PARP inhibition. Our results suggest that, at therapeutically relevant concentrations, the cytotoxicity of the platinum compound dominated over that of the PARP inhibitor and the PI3K inhibitor, even though a regression-based model could have indicated an overall synergy at lower and/or higher concentrations.
三阴性乳腺癌（TNBC）预后较差，因为其治疗存在多种局限性，最重要的是治疗耐药性。在这项研究中，我们研究了包括奥拉帕利（一种聚（ADP 核糖）聚合酶（PARP）抑制剂）、奥沙利铂（第三代铂化合物）和 LY294002（一种 Akt 通路抑制剂）在内的联合治疗对三阴性乳腺癌 MDA-MB-231 细胞系和激素受体阳性乳腺癌 MCF7 细胞系的不同反应。我们以单一、治疗相关浓度单独和以所有可能的组合应用这些药物，并评估了细胞活力、细胞死亡类型、活性氧产生、细胞周期阶段、集落形成和侵袭性生长。与文献一致，MDA-MB-231 细胞比 MCF7 细胞更具治疗耐药性。然而，与其他人的发现相反，我们没有检测到奥拉帕利和奥沙利铂之间的协同作用，并且我们发现 Akt 通路抑制剂增强了铂化合物的细胞抑制特性和/或防止了 PARP 抑制的细胞保护作用。我们的结果表明，在治疗相关浓度下，铂化合物的细胞毒性超过了 PARP 抑制剂和 PI3K 抑制剂的细胞毒性，尽管基于回归的模型可能表明在较低和/或较高浓度下存在整体协同作用。
