Redox State Determines the Differential Effects of Redox-Cycle Compounds in Chemoresistant Ovarian Cancer Cells

Resistance to platinum-based drugs (i.e., carboplatin) is a major clinical challenge in the current treatment of serous ovarian cancer. The molecular mechanisms underlying resistance are not yet fully clarified. In this study, we investigated whether the differences in redox state (levels of antioxidants and ROS) is correlated with carboplatin resistant phenotype of ovarian cancer cells (OV90C). We found that OV90C cells exhibited an oxidized redox state with a high level of H 2 O 2 but a low level of GPxs and reduced form of thioredoxin 1. Furthermore, OV90C cells displayed an increase of O 2 consumption and oxidative phosphorylation activity when compared to their parental cancer cells (OV90) and immortalized ovarian cells (hTER7). Next, we used MnTnBuOE-2-PyP 5+ (MnP), a redox- active MnSOD mimetic to investigate the dependence of ovarian cancer cell growth on the redox state. We found that OV90C cells preferentially uptake MnP more than OV90 cells, resulting in a greater inhibition of cell growth in OV90C cells versus OV90 cells. Combination treatment of MnP and carboplatin enhanced the killing effect of carboplatin in both OV90C cells and OV90 cells when compared to either MnP or carboplatin treatment alone. Moreover, MnP protected hTER7 cells from carboplatin-induced cell death. Mechanistically, the carboplatin enhanced redox cycle ability of MnP; which led to the induction of H 2 O 2 levels and reduction of GSH/GSSG ratio, in ovarian cancer cells but not in normal cells. Thus, increasing of oxidized redox state sensitized ovarian cancer cells to carboplatin, especially carboplatin resistant cells. In conclusion, our data provide evidence that the oxidized redox state plays an important role in carboplatin resistant ovarian cancer cells survival and pushing ROS levels beyond their antioxidant capacity might serve as a novel treatment strategy for ovarian cancer patients with resistance toward platinum-based drugs.