Abstract 3719: Simultaneous targeting of ER-stress and PI3K/AKT pathways as novel anticancer and chemosensitization approach against castration resistant prostate cancer

Abstract

Abstract Prostate cancer (PCa) is the second leading cause of cancer-related deaths among men in the United States. The recurrence of castration resistant prostate cancer (CRPC) is a therapeutic challenge. Docetaxel (DTX) - based chemotherapy is the preferred first-line treatment for men with CRPC. However, DTX extends life expectancy by an average of only 2 months and manifests significant systemic toxicities. Hence, there is a need to evaluate safer agents for CRPC, either as an adjunct treatment to decrease DTX doses or as a chronic regimen following DTX treatment to prevent tumor recurrence. Enhanced tumor-specific killing may be achieved by targeting multiple metabolic pathways that are critical to tumor growth and survival. The inherent Endoplasmic Reticulum (ER) stress and PI3K/AKT pathways are crucial survival mechanisms in aggressive tumors, such as CRPCs. We hypothesize that simultaneous induction of ER-stress and suppression of PI3K/AKT pathway by clinically approved drugs, such as Nelfinavir (NFR) and Curcumin (CUR), will be a very effective antitumor and chemosensitization strategy against CRPCs. NFR is a clinically approved HIV-1 protease inhibitor and CUR is a phytochemical used as a safe dietary supplement. Individually, both drugs possess antiproliferative properties against cancer cells and induce severe ER-stress and suppress PI3K/AKT pathways; however, the doses needed are supra-physiological. Therefore, we have investigated whether coexposure to NFR and CUR at physiologically achievable concentrations (<10 μM) will manifest anticancer and chemosensitizing effects in CRPCs. Two well-known CRPC cell lines, C4-2B and PC-3, were used in this study. Following 72 hr exposure, MTT-assays showed a 79% decrease in cell viability when C4-2B cells were exposed to NFR (5µM) and CUR (5µM) in combination with DTX (10nM), as compared to the drugs alone (NFR - 25%, CUR - 26%, DTX - 44%). A decrease in activated AKT (phosphorylated) was also observed in presence of these drug combinations. Western blot analyses for ER stress markers, e. g. CHOP and phospho-PERK, showed that cells exposed to NFR and CUR combinations had a 2.42 and 6.3 fold increase, respectively. Colony Forming Units (CFU) assay showed a 79% reduction in percent colonies in C4-2B cells chronically (2 wks) exposed to the NFR (5µM) and CUR (5µM) combinations, as compared to the drugs alone (NFR - 37%, CUR - 23%), suggesting long-term antitumor effect following chemotherapy. Combined treatment with NFR and CUR showed a much lower toxicity towards Mesenchymal Stem cells (MSCs) and primary endothelial cells, implicating their safety profiles. Taken together, our investigations suggest an antitumor regimen using two clinically approved agents, NFR and CUR, which can be used as an adjunct to DTX to sensitize CRPCs and as a safe chronic regimen to suppress tumor recurrence following chemotherapy. 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 3719. doi:1538-7445.AM2012-3719