Enhancing cytotoxic therapies for breast and prostate cancers with polyunsaturated fatty acids.

The role of omega-3 and omega-6 fatty acids has been extensively studied in most of the human malignancies including breast, colon, prostate, pancreas, and stomach cancers. In particular, the role of omega-3 and omega-6 fatty acids in carcinogenesis has been extensively investigated in epidemiological, laboratory cell culture studies and studies in vivo in animal. Findings from these studies suggest that omega-3 and omega-6 fatty acids are cytotoxic in different cancers and act synergistically with cytotoxic drugs. Although experimental evidence for the potential beneficial role of polyunsaturated fatty acids (PUFAs) in enhancing the effectiveness of various chemotherapeutic agents in animal models and in cell culture studies is increasing, there are only a few reports that have shown supportive evidence for linking these natural compounds with augmentation of anticancer chemotherapeutics in human trials. This review presents evidence for a commonality in the proposed molecular mechanisms of action elicited by various PUFAs believed to be responsible for their enhancement of the effectiveness of anticancer chemotherapy, specifically in breast and prostate cancers, and reviews laboratory and animal studies and few reported human clinical trials. It concludes that sufficient evidence is available to suggest that major clinical trials with these natural compounds as adjuncts to standard therapies should be undertaken as a priority.

Docosahexaenoic acid enhances the efficacy of docetaxel in prostate cancer cells by modulation of apoptosis: the role of genes associated with the NF-kappaB 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-kappaB 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-kappaB 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-kappaB pathway. This highlights the possibility of developing such combination modalities for treatment of prostate cancer.