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.