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 ω-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, 22:6ω-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 (20:5ω-3). Overall, our findings suggest that the combination of CDDP treatment with a dietary supplementation with ω-3 polyunsaturated fatty acids could potentially represent a new therapeutic strategy for overcoming CDDP resistance in metastatic melanoma.
aDepartment of Radiology and Oncology, Center for Translational Research in Oncology (LIM24), Cancer Institute of São Paulo, School of Medicine of São Paulo University, São Paulo
bCell Culture Laboratory, FURG, Postgraduation Program in Physiological Sciences, Institute of Biological Sciences, Rio Grande, Universidade Federal do Rio Grande, Brazil
cInstitute of General Pathology, Università Cattolica del Sacro Cuore
dFondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
*Renata Ottes Vasconcelos and Simona Serini contributed equally to the writing of this article.
Correspondence to Gabriella Calviello, PhD, Institute of General Pathology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168 Roma, Italy Tel: +39 063 015 4914; fax: +39 063 386 446; e-mail: firstname.lastname@example.org
Received August 28, 2018
Accepted November 15, 2018