Abstract 2652: Effect of selective serotonergic reuptake inhibitors on radiation therapy

Abstract

Abstract Introduction: Selective serotonergic reuptake inhibitors (SSRIs) are well-established antidepressants commonly used in cancer patients. Studies suggest that SSRIs may play a role in increased cell death in cancer cells; however, the use of SSRIs as adjunctive agents to be used in combination with conventional cancer treatment is not well established. The purpose of this study was to evaluate the effect of SSRIs on cell survival in combination with radiation therapy (XRT). Methods: Human lung cancer lines (A-549 and H-460) and squamous oropharyngeal cancer cells (FaDu) were treated with several dose escalated SSRIs (fluoxetine, sertraline, paroxetine) alone or in combination with dose escalated XRT (0,2,4,6 Gy) to evaluate the cytotoxic effects of SSRIs using clonogenic survival assays. Western blot analysis was used to evaluate apoptosis (cleaved Caspase-3 and cleaved PARP) and autophagy (LC3-II) to assess potential mechanisms of the effects of SSRIs on XRT. Results: Fluoxetine, paroxetine, or sertraline alone had a cytotoxic effect on cancer cells in a concentration dependent manner. Sertraline and paroxetine at 2.5-5uM appeared to have an additive effect on XRT with severe cytotoxicity noted at higher concentrations. In contrast, fluoxetine appeared to have a sensitizing effect on cells at 1-10uM in a tumor cell specific manor. Western blot analysis demonstrated that fluoxetine administration decreased cleaved Caspase-3 and cleaved PARP expression at 24 or 48 hours. Evaluation of autophagy using LC3-II demonstrated no change with XRT; however, treatment with fluoxetine increased the expression of LC3-II at 24 and 48 hours in the presence or absence of XRT. Conclusions: Most SSRIs appear to have a cytotoxic effect alone or in combination with XRT. Fluoxetine appears to have a unique sensitizing effect on XRT in cancerous cells possibly through an increased induction of autophagy. Data supports further examination of fluoxetine as an adjunctive agent in combination with XRT. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2652. doi:10.1158/1538-7445.AM2011-2652