Fasting boosts sensitivity of human skin melanoma to cisplatin-induced cell death.
Melanoma is one of leading cause of tumor death worldwide. Anti-cancer strategy includes combination of different chemo-therapeutic agents as well as radiation; however these treatments have limited efficacy and induce significant toxic effects on healthy cells. One of most promising novel therapeutic approach to cancer therapy is the combination of anti-cancer drugs with calorie restriction. Here we investigated the effect Cisplatin (CDDP), one of the most potent chemotherapeutic agent used to treat tumors, in association with fasting in wild type and mutated BRAFV600Emelanoma cell lines. Here we show that nutrient deprivation can consistently enhance the sensitivity of tumor cells to cell death induction by CDDP, also of those malignancies particularly resistant to any treatment, such as oncogenic BRAF melanomas. Mechanistic studies revealed that the combined therapy induced cell death is characterized by ROS accumulation and ATF4 in the absence of ER-stress. In addition, we show that autophagy is not involved in the enhanced sensitivity of melanoma cells to combined CDDP/EBSS-induced apoptosis. While, the exposure to 2-DG further enhanced the apoptotic rate observed in SK Mel 28 cells upon treatment with both CDDP and EBSS.
Department of Pharmacology, Federal University of São Paulo, Brazil.
Fernanda
F
Antunes
Department of Biology, University of Rome "Tor Vergata", Italy; National Institute for Infectious Diseases IRCCS "Lazzaro Spallanzani", Italy. Electronic address: marco.corazzari@uniroma2.it.
Marco
M
Corazzari
Department of Pharmacology, Federal University of São Paulo, Brazil.
Gustavo
G
Pereira
Department of Biology, University of Rome "Tor Vergata", Italy; Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Lecce, 73100, Italy.
Gian Maria
GM
Fimia
Department of Biology, University of Rome "Tor Vergata", Italy; National Institute for Infectious Diseases IRCCS "Lazzaro Spallanzani", Italy. Electronic address: mauro.piacentini@uniroma2.it.
Mauro
M
Piacentini
Department of Pharmacology, Federal University of São Paulo, Brazil.
Soraya
S
Smaili
D000970:Antineoplastic Agents / Q000494:pharmacology*; D031204:Caloric Restriction; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D005215:Fasting; D006801:Humans; D008545:Melanoma / Q000178:diet therapy / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012867:Skin / Q000187:drug effects / Q000473:pathology; D012878:Skin Neoplasms / Q000178:diet therapy / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000096142:Cutaneous Malignant Melanoma
D000970:Antineoplastic Agents; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D002945:Cisplatin
Apoptosis; BRAF; CDDP; Melanoma; Starvation