Prostate cancer is currently the second leading cause of death from cancer among men in the United States. Initial treatments generally focus on hormone therapy to inhibit the production of androgens, but most prostate cancers eventually become castration resistant and no longer respond to androgen-suppression therapy. The recent development of drugs that inhibit androgen binding to the androgen receptor (AR) have proven effective in treating castration-resistant prostate cancer (CRPC). Studies in our laboratory have shown that docosahexaenoic acid (DHA; C22:6 n-3), a long chain omega-3 polyunsaturated fatty acid (PUFA), inhibits tumorigenesis in both androgen-dependent (LNCaP) and androgen-independent (PC-3, DU145) prostate cancer cell lines in culture. Moreover, in vivo studies with n-3 PUFA supplementation have been shown to significantly reduce tumor growth of PC-3 and DU145 compared to corn oil diets rich in linoleic acid, (C18:2, n-6). With evidence suggesting that n-3 PUFA dietary supplementation can inhibit tumorigenesis in CRPC, the current study investigated the impact of DHA supplementation in combination with enzalutamide in PC-3 tumor cells. Enzalutamide is a Food and Drug Administration-approved treatment for patients with metastatic CRPC. Enzalutamide acts by interrupting the binding of androgens to the AR, which influences the AR signaling pathway–a target of interest in CRPC treatment. Cell viability was determined by measuring intracellular ATP in PC-3 cells treated with DHA and enzalutamide alone and in combination. Cell viability was reduced with the combination of DHA and enzalutamide compared to enzalutamide or DHA alone, suggesting that DHA enrichment can augment enzalutamide therapy with PC-3 cells in vitro. Studies have also shown that combinatorial treatments with enzalutamide and HIF-1α inhibitors result in synergistic inhibition of CRPC tumor proliferation, and our laboratory has shown that DHA inhibits HIF-1α by decreasing intracellular ATP in breast and lung cancer cells in vitro. These results serve as a prelude to a pilot clinical trial to evaluate the effects of nutritional supplementation with high levels of omega-3 fatty acids on enzalutamide inhibition of CRPC.

Citation Format: Irvin V. Ma, Andrew R. Cooper, Ying Hu, Arianne G. Sorreta, Palvinder K. Bains, Prem Kumar, Ronald S. Pardini. Docosahexaenoic acid supplementation enhances the response of PC-3 prostate cancer cells to enzalutamide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1272.