Abstract 4657: Differential regulation of autophagy vs. apoptosis as a potentially unique mechanism of cancer cell specific radiosensitization with fluoxetine

Abstract

Abstract Introduction: Prior data demonstrate that selective serotonergic reuptake inhibitors (SSRIs) are cytotoxic to cancer cells and that fluoxetine can sensitize cells to radiotherapy (XRT) potentially through induction of autophagy; however, there is limited information on the effects of serotonergic receptor modulation and mechanisms of other SSRIs on cytotoxicity with radiotherapy. Methods: Human lung cancer lines (A549 and H460) and oropharyngeal cancer cells (FaDu) were treated with dose escalated SSRIs (fluoxetine, sertraline, paroxetine), serotonergic receptor (5-HTR) agonists (CP809101, S14506), or 5-HTR antagonists (agomelatine, spiroxatrine) alone or in combination with dose escalated XRT to evaluate the effects of on cell survival using clonogenic survival assays. 5-HTR expression, apoptosis, and autophagy were evaluated as 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. Fluoxetine had a sensitizing effect in combination with XRT in a cell specific manor; however, sertraline and paroxetine had an additive cytotoxic effect on XRT. 5-HTR agonists and antagonists did not demonstrate any significant sensitizing effects, but agonists were cytotoxic at 10-50 uM with no apparent cytotoxicity from antagonists. Western blot analysis demonstrated that fluoxetine, paroxetine, or sertraline decreased apoptosis (cleaved caspase-3 and cleaved PARP) and increased autophagy (LC3B-II) in H460 cells associated with the sensitizing effect of fluoxetine on XRT. In contrast, the additive cytotoxicity of sertraline or paroxetine was not associated with a differential regulation of apoptosis vs. autophagy in A549 cells. Conclusions: SSRIs appear to have a cytotoxic effect alone or in combination with XRT potentially through a non 5-HTR based mechanism. The cell specific differential regulation of apoptosis vs. autophagy associated with fluoxetine warrants further examination of a potentially unique mechanism of radiosensitization. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4657. doi:1538-7445.AM2012-4657