Fasting boosts sensitivity of human skin melanoma to cisplatin-induced cell death

Biochem Biophys Res Commun. 2017 Mar 25;485(1):16-22. doi: 10.1016/j.bbrc.2016.09.149. Epub 2016 Sep 29.

Abstract

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 BRAFV600E melanoma 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.

Keywords: Apoptosis; BRAF; CDDP; Melanoma; Starvation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Caloric Restriction
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • Fasting*
  • Humans
  • Melanoma / diet therapy
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / pathology
  • Mutation
  • Proto-Oncogene Proteins B-raf / genetics
  • Skin / drug effects
  • Skin / pathology
  • Skin Neoplasms / diet therapy
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology

Substances

  • Antineoplastic Agents
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Cisplatin

Supplementary concepts

  • Melanoma, Cutaneous Malignant