Abstract 1525: RLIP76 transports sunitinib and sorafenib and mediates drug resistance in kidney cancer

Abstract

Abstract RLIP76 is a stress-responsive membrane protein implicated in the regulation of multiple cellular signaling pathways. It functions as the predominant glutathione-electrophile conjugate (GS-E) transporter in cells. We have shown that RLIP76 plays a crucial role in defending cancer cells from radiation and chemotherapeutic toxin-mediated apoptosis, and its inhibition by antibodies or depletion by siRNA or antisense causes apoptosis in a number of cancer cell types. Recently, we have demonstrated for the first time the striking anti-neoplastic effects with no evident toxicity in terms of either weight loss or metabolic effects for the antibody, antisense and siRNA in a renal cell xenografts model of Caki-2 cells (Singhal et al., Cancer Res., 2009, 69: 4244). Present studies were performed to determine if RLIP76 targeting is more broadly applicable in other kidney cancer cell lines, to compare the signaling effects of RLIP76 antisense with kinase inhibitors used in treatment of renal cell carcinoma, and to determine whether kinase inhibitors were substrates for transport by RLIP76. Results of these studies show that sorafenib as well as sunitinib are substrates for transport by RLIP76 thus are competitive inhibitors of GS-E transport. Furthermore, kinase inhibition in the ERK as well as PI3K pathways by RLIP76 depletion is more profound and consistent and is more widely apparent in a number of renal carcinoma cell lines. These studies support the validity of RLIP76 as a target in kidney cancer therapy, and the functional model in which RLIP76 provides protection from chemical and radiant stress through its transport activity. Results of these studies revealed for the first time that sorafenib as well as sunitinib, receptor tyrosine kinase inhibitors (RTKIs), are substrates for transport by RLIP76. These studies offer strong support for our overall hypothesis that RLIP76 is an overarching anti-apoptosis mechanism that, if inhibited, can be more broadly effective in the treatment of renal cell carcinoma. (Supported in part by NIH Grants CA 77495 and CA 104661 (to SA), Cancer Research Foundation of North Texas (to SSS & SY), Institute for Cancer Research and the Joe & Jessie Crump Fund for Medical Education (to SSS)) 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 1525.