Docosahexaenoic Acid Enhances the Cytotoxic Effects of Enzalutamide and the PARP Inhibitor in Castration-Resistant Prostate Cancer Cell Lines

Docosahexaenoic acid (DHA), an omega-3 fatty acid, has emerged as a promising adjuvant treatment for castration-resistant prostate cancer (CRPC), but its interactions with current therapies remain unclear. This study investigated the antitumor effects of DHA alone or in combination with enzalutamide (ENZ) or the PARP inhibitor AZD2461 (iP) in CRPC cell lines 22Rv1 and PC3. DHA enhanced the cytotoxic effect of iP in both cell lines and of ENZ in 22Rv1 cells. In PC3 cells, DHA-mediated potentiation of iP cytotoxicity was associated with downregulation of the AKT pathway, reduced expression of ERα and the lipid sensors PPARγ and LXRβ, and a shift in programmed cell death toward necroptosis. In 22Rv1 cells, the additive effects of DHA with ENZ or iP were independent of PI3K/pAKT and AR-FL/AR-V7 modulation but were associated with regulation of LXRβ, PPARγ, and TNFR1, along with activation of apoptosis. Wound-healing assays showed that DHA blocked the anti-migratory effects of ENZ and iP in 22Rv1 cells and did not alter iP effects in PC3 cells, indicating epithelial–mesenchymal transition heterogeneity. Overall, DHA potentiates the cytotoxic effects of iP in both models and of ENZ in 22Rv1 cells via differential modulation of cell death in a molecular context-dependent manner.