Abstract 4778: Resveratrol suppresses constitutive activation of AKT via generation of reactive oxygen species and induces apoptosis in diffuse large B cell lymphoma cell lines

Abstract

Abstract We have recently shown that deregulation PI3-kinase/AKT survival pathway plays an important role in the pathogenesis of diffuse large B cell lymphoma (DLBCL). In an attempt to identify newer agents that can be utilized to target these deregulated pathways, we found that Resveratrol (trans-3,4′, 5-trihydroxystilbene) is a naturally occurring polyphenolic compound that has an antioxidant and chemopreventive effects on various cancer cells. In the current investigation, we therefore investigated the role of resveratrol-mediated chemopreventive effect on various DLBCL cell lines. Resveratrol caused a dose dependent inhibition of cell viability in DBCL cell lines. To see whether this inhibition was due to cell cycle arrest or apoptosis, we found that resveratrol induced apoptosis in all DLBCL cell lines. We next investigated the action of resveratrol on PI3-kinase/AKT pathway and found that resveratrol treatment resulted in inhibition of constitutively activated AKT and its downstream targets, p-FOXO1, p-GSK3 and p-Bad via generation of reactive oxygen species (ROS). Inactivation of Bad led to conformational changes in Bax protein causing loss of mitochondrial membrane potential and release of cytochrome c to the cytosol. This led to activation of caspase-9, caspase-3, and poly-(ADP)-ribose polymerase cleavage leading to caspase-dependent apoptosis. In addition, resveratrol treatment of DLBCL cell lines also caused ROS dependent upregulation of DR5; however, this up-regulation did not result in apoptosis. Finally, co-treatment of DLBCL with sub-toxic doses of TRAIL and resveratrol induced efficient apoptosis. Altogether, these data suggest a novel function for resveratrol, acting as a suppressor of AKT/PKB pathway via generation of ROS in DLBCL cells, and raise the possibility that this agent may have a future therapeutic role in DLBCL and possibly other malignancies with constitutive activation of the AKT/PKB pathway either alone or in combination with other chemotherapeutic agents. 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 4778. doi:10.1158/1538-7445.AM2011-4778