Combination of omega-3 fatty acids and cisplatin as a potential alternative strategy for personalized therapy of metastatic melanoma: an in-vitro study

The recently developed therapeutic strategies have led to unprecedented improvements in the control of metastatic melanoma and in the survival of specific subgroups of patients. However, drug resistance, low response rates, and undesired side effects make these treatments not suitable or tolerable for all the patients, and chemotherapeutic treatments appear still indispensable, at least for subgroups of patients. New combinatory strategies are also under investigation as tailored treatments or salvage therapies, including combined treatments of immunotherapy with conventional chemotherapy. On this basis, and in consideration of the antineoplastic properties of omega-3 polyunsaturated fatty acids, we have here investigated the potential of these bioactive dietary factors to revert the resistance frequently exhibited by this form of cancer to cisplatin (CDDP, cis-diamminedichloroplatinum). We demonstrated that docosahexenoic acid (DHA, 22:6 omega-3) sensitizes the cells to the CDDP-induced inhibition of cell growth and migration by reverting CDDP effects on DNA damage and ERCC1 expression, as well as on the DUSP6 and p-ERK expressions, which regulate ERCC1 activation upwardly. In line, DUSP6 gene silencing prevented the effect of DHA, confirming that DHA acted on the DUSP6/p-ERK/ERCC1 repair pathways to sensitize melanoma cells to the anticancer effect of CDDP. Similar effects were obtained also with eicosapentaenoic acid (20:5 omega-3). Overall, our findings suggest that the combination of CDDP treatment with a dietary supplementation with omega-3 polyunsaturated fatty acids could potentially represent a new therapeutic strategy for overcoming CDDP resistance in metastatic melanoma. (AU)