Multiple studies have shown that psychological distress in epithelial ovarian cancer (EOC) patients is associated with worse quality of life and poor treatment adherence. This may influence chemotherapy response and prognosis. Moreover, although stress hormones can reduce cisplatin efficacy in EOC treatment, their effect on the integrity of DNA remains poorly understood. In this study, we investigated whether norepinephrine and epinephrine can induce DNA damage and modulate cisplatin-induced DNA damage in three EOC cell lines. Our data show that norepinephrine and epinephrine exposure led to increased nuclear γ-H2AX foci formation in EOC cells, a marker of double-strand DNA breaks. We further characterized norepinephrine-induced DNA damage by subjecting EOC cells to alkaline and neutral comet assays. Norepinephrine exposure caused DNA double-strand breaks, but not single-strand breaks. Interestingly, pre-treatment with propranolol abrogated norepinephrine-induced DNA damage indicating that its effects may be mediated by β-adrenergic receptors. Lastly, we determined the effects of norepinephrine on cisplatin-induced DNA damage. Our data suggest that norepinephrine reduced cisplatin-induced DNA damage in EOC cells and that this effect may be mediated independently of β-adrenergic receptors. Taken together, these results suggest that stress hormones can affect DNA integrity and modulate cisplatin resistance in EOC cells.

According to the American Cancer Society, ovarian cancer is the deadliest cancer of the female reproductive system. Moreover, a significant number of ovarian cancer patients are clinically depressed or lack social support at the time of their diagnosis. Mounting data support an association between chronic stress and depression with sustained sympathetic nervous system activation (SNS). Furthermore, there is strong evidence supporting a relationship between prolonged SNS activation and cancer progression. In addition, work from our group and others has shown that psychological states such as chronic stress or depression accelerate the growth of existing tumors and promote chemoresistance. Also, recent data from our lab shows that exposure to norepinephrine (NE) leads to double‐stranded DNA breaks in epithelial ovarian cancer cells (EOC) in a β‐adrenergic receptor‐dependent manner. Interestingly, when EOC were co‐exposed to NE and cisplatin (a DNA damaging agent used in ovarian cancer therapy), we observed fewer double‐stranded DNA breaks than with either treatment alone. These data suggest that stress hormones could influence EOC responses to chemotherapeutic agents. Here, we sought to determine the contribution of adrenergic signaling to Olaparib (an FDA‐approved PARP inhibitor) resistance in EOC. We first determined the EOC viability after exposure to Olaparib. Here, we exposed ES‐2 ovarian cancer cells to serial dilutions of Olaparib and calculated their viability after 48 hrs, 72 hrs, 96 hrs, and 120 hrs. Following each experiment, we calculated the IC50 for each timepoint. Our preliminary data suggest an IC50 of 19µM at 48 hrs, 28.5 µM at 72 hrs, 14.5 µM at 96 hrs, and 8 µM at 120 hrs. Currently, we are performing additional experiments to expand these preliminary data to other EOC lines and further determine the contribution of NE to Olaparib resistance in EOC.