Mitochondrial Oxidative Stress as a Novel Therapeutic Target to Overcome Intrinsic Drug Resistance in Melanoma Cell Subpopulations

Exp Dermatol. 2015 Feb;24(2):155-7. doi: 10.1111/exd.12613.

Abstract

Despite recent success in melanoma therapy, most patients with metastatic disease still undergo deadly progression. We have identified a novel mechanism of multidrug resistance allowing a small subpopulation of slow-cycling melanoma cells to survive based on elevated oxidative bioenergy metabolism. In this study, we asked whether such slow-cycling cells could be eliminated by co-treatment with the copper-chelator elesclomol. Elesclomol-copper complexes can cause oxidative stress by disruption of the mitochondrial respiration chain or by indirect non-mitochondrial induction of reactive oxygen species. We have found that elesclomol effectively kills the slow-cycling subpopulation and prevents the selective enrichment for slow-cycling cells, which usually results after monotreatment. We hypothesize that elesclomol could overcome the multidrug resistance of slow-cycling melanoma cells and prevent tumor repopulation in melanoma patients in future.

Keywords: melanoma; mitochondria; reactive oxygen species; therapy resistance; tumor heterogeneity.

Publication types

  • Letter
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Chelating Agents / chemistry
  • Copper / chemistry
  • Disease Progression
  • Disease-Free Survival
  • Drug Resistance, Multiple*
  • Drug Resistance, Neoplasm*
  • Genotype
  • Humans
  • Hydrazines / chemistry
  • Hydrazines / pharmacology*
  • Melanoma / metabolism*
  • Mitochondria / metabolism*
  • Oxidative Stress / drug effects*
  • Oxygen / chemistry
  • Reactive Oxygen Species / chemistry
  • Skin Neoplasms / metabolism

Substances

  • Antineoplastic Agents
  • Chelating Agents
  • Hydrazines
  • Reactive Oxygen Species
  • elesclomol
  • Copper
  • Oxygen