Abstract 3259: HIV protease inhibitors induce apoptotic and non-apoptotic cell death in ovarian cancer cells in vitro and in vivo

Abstract

Abstract Introduction: HIV patients taking antiretroviral protease inhibitors have a lower incidence of HIV associated malignancies, leading to the hypothesis that these drugs have antineoplastic activity. Given the need for novel treatment approaches in ovarian cancer, we investigated the antineoplastic effects of the HIV protease inhibitors saquinavir and nelfinavir in vitro and in vivo. Methods: A panel of ovarian cancer cell lines was treated with saquinavir and nelfinavir. The effect of protease inhibitors on cell growth, viability, apoptotic and non-apoptotic cell death was determined. Stimulation of endoplasmic reticulum stress (ERS) response was assessed by immunoblotting for ERS regulators GRP78 and ATF6. Induction of autophagy was assessed using transmission electron microscopy (TEM), and confocal microscopy was performed to demonstrate changes in green fluorescent protein-labeled LC3 expression patterns. A xenograph model of ovarian cancer was used to assess the antineoplastic effect of nelfinavir in vivo. Results: HIV protease inhibitors induced cell death in chemosensitive and chemoresistant ovarian cancer cells in a time- and dose-dependent manner. Treatment with protease inhibitors resulted in caspase-dependent apoptosis and caspase-independent cell death characterized by induction of ERS and autophagy. Cellular morphology assessed by TEM revealed apoptotic, autophagic, and necrotic cell death. Preliminary results indicate that nelfinavir administer intraperitoneally inhibits tumor growth in vivo without inducing weight loss. In contrast, the dose of intraperitoneal cisplatin required to attain a similar antineoplastic effect resulted in significant weight loss and morbidity. Conclusions: Because protease inhibitors can induce both apoptotic and non-apoptotic cell death, these drugs may circumvent chemoresistance due to alterations in apoptotic response. Saquinavir and Nelfinavir are FDA-approved agents for the treatment of HIV, and our data suggest that these drugs may also have clinical application in the treatment of ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3259.