Abstract B42: Nelfinavir potentiates the anti-cancer efficacy of curcumin by subverting endoplasmic reticulum stress toward apoptosis: A promising chemoprevention approach

Abstract

Abstract Prostate cancer (PCa) is the second leading cause of cancer-related deaths among men in the United States. Despite the availability of treatments against localized PCa, the clinical management of advanced PCa remains a significant challenge in relation to both patient morbidity and escalating healthcare costs. Therefore, the ability to suppress cancer growth using safe natural compounds as chemopreventive agents, e.g. Curcumin (CUR), is emerging as a promising and cost-effective approach. The anti-cancer effects of CUR have been associated with its ability to suppress crucial survival pathways in cancer cells, e.g. PI3K/Akt and NF-κB signaling. However, clinical trials investigating the anti-cancer potential of CUR have clearly indicated that this phytochemical will be of limited efficacy when used alone. Aggressive cancer cells utilize multiple master regulatory pathways to dictate their growth, survival and death decisions, which need to be simultaneously targeted towards an effective anti-cancer approach. Indeed, recent findings demonstrate that the control of cell survival and apoptosis is exquisitely regulated via the endoplasmic reticulum (ER) stress cascades. Numerous recent studies have shown that the clinically approved HIV-1 protease inhibitor drug, Nelfinavir (NFV) is an well-tolerated oral drug with promising anti-cancer properties. The antitumor effects of NFV is believed to be via the suppression of PI3K/Akt and the induction of ER-stress. Therefore, we hypothesized that the constitutive ER-stress in aggressive cancer cells can be subverted towards apoptosis by chronic exposure to CUR and NFV, which will be a novel chemoprevention approach. In vitro studies (MTT cytotoxicity-assays) in two aggressive PCa cell lines, i.e. C4-2B and PC-3, showed significant (p<0.05) increases in cytotoxicity following coexposure to physiologically achievable concentrations of CUR & NFV (5 μM each). However, this drug combination did not show comparable toxicity in the non-tumorigenic RWPE-1 cell line, or in the primary prostate epithelial cells (PrEC) and bone-marrow mesenchymal stem cells (MSC). Western immunoblot studies showed that combined exposure to CUR & NFV acted in a synergistic manner (combination index<1) to suppress Akt activation (phosphorylated form) and significantly (p<0.05) increased the levels of early ER-stress markers, Grp78 and phospho-eIF2α. The ER-stress induced pro-apoptotic markers, i.e. ATF4, CHOP, and TRIB3 were also upregulated following acute (12 hr) exposure to CUR & NFV combination. More importantly, chronic exposure (3 wks; replenished every third day) to a much lower concentration of CUR & NFV combination (0.5 μM each) was able to drastically reduce the clonogenic ability of C4-2B and PC-3 cells, as evident from colony forming unit (CFU) assays. Therefore, our in vitro studies showed that NFV can potentiate the anti-cancer effects of CUR and this combination may be a promising approach against PCa growth. In vivo studies using mice containing C4-2B tumor xenografts (<50 mm) are currently in progress to document the safety and anti-tumor efficacy of chronic treatment with the CUR & NFV combination. Initial evidence of the in vitro efficacy of this combination suggests a safe chemoprevention strategy that specifically targets the constitutive ER-stress in aggressive cancer cells. Citation Format: Aditi Mathur, Mikhail L. Kostochka, Asim B. Abdel-Mageed, Debasis Mondal. Nelfinavir potentiates the anti-cancer efficacy of curcumin by subverting endoplasmic reticulum stress toward apoptosis: A promising chemoprevention approach. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B42.