Mitochondrial oxidative stress as a novel therapeutic target to overcome intrinsic drug resistance in melanoma cell subpopulations

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.