title: Suppression of B-RafV600Emelanoma cell survival by targeting mitochondria using triphenyl-phosphonium-conjugated nitroxide or ubiquinone.
abstract: Most BRAF-mutated melanomas initially responsive to the FDA-approved inhibitors preferentially targeting B-Raf mutated in Val600 residue eventually relapse, requiring additional therapeutic modalities. Recent studies report the significance of metabolic reprograming in mitochondria for maintenance of BRAF-mutated melanomas and for development of their drug resistance to B-Raf inhibitors, providing a rationale for targeting mitochondria as a potential therapeutic strategy for melanoma. We therefore determined whether mitochondria-targeted metabolism-interfering agents can effectively suppress human B-RafV600Emelanoma cell lines and their dabrafenib/PLX4032-resistant progenies using mitochondria-targeted carboxy-proxyl (Mito-CP) and ubiquinone (Mito-Q). These agents exhibited comparable efficacy to PLX4032 in suppressing SK-MEL28, A375, and RPMI-7951 cells in vitro. As determined in SK-MEL28 and A375 cells, Mito-CP induced apoptotic cell death mediated by mitochondrial membrane depolarization and subsequent oxidative stress, which PLX4032 could not induce. Of note, Mito-CP also effectively suppressed PLX4032-resistant progenies of SK-MEL28 and A375. Moreover, when orally administered, Mito-CP suppressed SK-MEL28 xenografts in mice as effectively as PLX4032 without serious adverse effects. These data demonstrate that mitochondria-targeted agents have therapeutic potential to effectively suppress BRAF-mutated melanomas via an effect(s) distinct from those of B-Raf inhibitors.
authors: a Department of Biochemistry , Medical College of Wisconsin , Milwaukee , WI , USA.
authors: Seung-Keun
authors: SK
authors: Hong
authors: a Department of Biochemistry , Medical College of Wisconsin , Milwaukee , WI , USA.
authors: Dmytro
authors: D
authors: Starenki
authors: a Department of Biochemistry , Medical College of Wisconsin , Milwaukee , WI , USA.
authors: Pui-Kei
authors: PK
authors: Wu
authors: a Department of Biochemistry , Medical College of Wisconsin , Milwaukee , WI , USA.
authors: Jong-In
authors: JI
authors: Park
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008545:Melanoma / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D014451:Ubiquinone / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D014451:Ubiquinone; D048493:Proto-Oncogene Proteins B-raf
keywords: B-Raf; Mito-CP; Mito-Q; drug resistance; melanoma; mitochondria