Characterizing the Contribution of Adrenergic Signaling to Olaparib Resistance in Ovarian Cancer 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. © FASEB.