Docosahexaenoic Acid Enhances the Efficacy of Docetaxel in Prostate Cancer Cells by Modulation of Apoptosis: The Role of Genes Associated With the NF-κB Pathway

BACKGROUND. Evidence is growing for beneficial interactions between omega-3 fatty acids from fish and chemotherapy agents in certain human cancers. Evidence for similar effects in prostate cancer is lacking. We investigated the effects of docosahexaenoic acid (DHA-22:6n-3), a component of fish oil, on the cytotoxicity of docetaxel in prostate cancer cells. METHODS. Cell viability was studied using the MTT assay and apoptosis was evaluated by flow cytometry using PI, annexin V, and JC-1 staining. Cellular signaling mechanisms that might explain the observed pro-apoptotic effects were investigated using NF-kappa B pathway specific cDNA microarrays and RT-PCR validation. RESULTS. DHA enhanced the pro-apoptotic efficacy of docetaxel, synergistically, in hormone receptor positive and negative LNCaP, DU145 and PC3 cells, respectively. Cell cycle analysis showed an increase in G2M arrest and JC-1 staining showed a significant (P < 0.018) increase in apoptotic cells with combination treatments in LNCaP cells. Microarray and RTPCR showed decreased expression of FADD, AKT1, MAX, TRAF3, MAP2k4, TNFRSF11A, and RIPK1 in LNCaP cells. Similar results were obtained with DU145 cells; combinations were more effective than single treatments. Combination treatments suppressed NF-kappa B signaling that was induced by docetaxel alone; this is considered an anti-apoptotic response. CONCLUSION. DHA synergistically enhanced the cytotoxic effect of docetaxel in prostate cancer cells through increased apoptosis by suppression of genes involved in the NF-kappa B pathway. This highlights the possibility of developing such combination modalities for treatment of prostate cancer. Prostate 68: 1635-1646, 2008. (C) 2008 Wiley-Liss, Inc.