title: 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.
authors.affiliation: Department of Dermatology, The Saarland University Hospital, Homburg/Saar, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Cierlitza
authors.forename: Heike
authors.initials: H
authors.lastname: Chauvistré
authors.forename: Ivan
authors.initials: I
authors.lastname: Bogeski
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Axel
authors.initials: A
authors.lastname: Hauschild
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogt
authors.forename: Alexander
authors.initials: A
authors.lastname: Roesch
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry; D003300:Copper / Q000737:chemistry; D018450:Disease Progression; D018572:Disease-Free Survival; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005838:Genotype; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology*; D008545:Melanoma / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010100:Oxygen / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000737:chemistry; D012878:Skin Neoplasms / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; D006834:Hydrazines; D017382:Reactive Oxygen Species; C512195:elesclomol; D003300:Copper; D010100:Oxygen
keywords: melanoma; mitochondria; reactive oxygen species; therapy resistance; tumor heterogeneity