DNA Double-Strand Break Repair Inhibitors: YU238259, A12B4C3 and DDRI-18 Overcome the Cisplatin Resistance in Human Ovarian Cancer Cells, but Not under Hypoxia Conditions

Abstract

Cisplatin (CDDP) is the cornerstone of standard treatment for ovarian cancer. However, the resistance of ovarian cancer cells to CDDP leads to an inevitable recurrence. One of the strategies to overcome resistance to CDDP is the combined treatment of ovarian cancer with CDDP and etoposide (VP-16), although this strategy is not always effective. This article presents a new approach to sensitize CDDP-resistant human ovarian carcinoma cells to combined treatment with CDDP and VP-16. To replicate the tumor conditions of cancers, we performed analysis under hypoxia conditions. Since CDDP and VP-16 induce DNA double-strand breaks (DSB), we introduce DSB repair inhibitors to the treatment scheme. We used novel HRR and NHEJ inhibitors: YU238259 inhibits the HRR pathway, and DDRI-18 and A12B4C3 act as NHEJ inhibitors. All inhibitors enhanced the therapeutic effect of the CDDP/VP-16 treatment scheme and allowed a decrease in the effective dose of CDDP/VP16. Inhibition of HRR or NHEJ decreased survival and increased DNA damage level, increased the amount of γ-H2AX foci, and caused an increase in apoptotic fraction after treatment with CDDP/VP16. Furthermore, delayed repair of DSBs was detected in HRR- or NHEJ-inhibited cells. This favorable outcome was altered under hypoxia, during which alternation at the transcriptome level of the transcriptome in cells cultured under hypoxia compared to aerobic conditions. These changes suggest that it is likely that other than classical DSB repair systems are activated in cancer cells during hypoxia. Our study suggests that the introduction of DSB inhibitors may improve the effectiveness of commonly used ovarian cancer treatment, and HRR, as well as NHEJ, is an attractive therapeutic target for overcoming the resistance to CDDP resistance of ovarian cancer cells. However, a hypoxia-mediated decrease in response to our scheme of treatment was observed.