Abstract 3704: Evaluation of curcumin in combination with 6-shogaol and epicatechin for the chemoprevention of prostate cancer.

Prostate cancer is the most frequently diagnosed malignancy in American men and second leading cause of cancer related death. Despite much recent progress, prostate cancer continues to represent a major cause of cancer-related mortality and morbidity in men. Various epidemiological data suggested the inverse relationship between the consumption of fruits and vegetables and the incidence of various cancers. Recently there has been increased interest in the use of phytochemicals for the prevention of cancer. In order to identify effective chemopreventive strategies for prostate cancer, we are evaluating the effectiveness of the combinations of promising dietary phytochemicals including curcumin (CURC) from turmeric with epicatechin (EC) from green tea and 6-shogaol (6-SHO) from ginger in human and mouse prostate cancer models. In the present study, we first measured the growth inhibitory effect and found that the combinations of both CURC+6-SHO and CURC+EC produced significantly higher inhibition of growth of human prostate cancer cells (LNCaP, DU145, PC-3) and cultured mouse prostate cells from Hi-Myc mice (HMVP-2 cells) compared to the individual compounds alone. Next, we measured the apoptosis inducing activity and found that both combinations induced apoptosis and cleavage of PARP more strongly than the individual compounds alone. To clearly understand the molecular mechanism of increased growth inhibition and apoptosis, we performed Western blot analyses and found that CURC+6-SHO inhibited activation of both constitutive and IL-6 induced Stat3 activation. Several Stat3 target molecules such as cyclinD1 and survivin levels are also decreased. The combinations also showed stronger inhibition of NF-κB and mTORC1 signaling pathways. Quantitative real-time PCR data showed that combinations of CURC+6-SHO further modulated the expression of cell cycle and apoptosis regulatory genes as well as certain chemokines and cytokines. We have recently established an allograft mouse model of prostate cancer by injecting the HMVP-2 cells into FVB mice. This model gives rise to palpable tumors within 10-14 days post injection. Since the combinations of CURC+6-SHO and CURC+EC appeared most effective from cell culture experiments, we are currently testing these combinations for their efficacy against HMVP-2 cells grown as allograft tumors in FVB/N mice. Taken together, our current findings suggest that combinations of CURC with 6-shogaol and EC showed greater activity than individual compounds alone in cultured cells. Ongoing in vivo studies to be presented will provide a better understanding of the efficacy and mechanisms of action for these combinations in chemoprevention of prostate cancer. A. Saha is supported by CPRIT training grant RP101501 Citation Format: Achinto Saha, Jorge Blando, Kaoru Kiguchi, John DiGiovanni. Evaluation of curcumin in combination with 6-shogaol and epicatechin for the chemoprevention of prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3704. doi:10.1158/1538-7445.AM2013-3704