Suppression of B-Raf^V600E melanoma 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-Raf melanoma 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.

Oxidative stress and antioxidants in the pathophysiology of malignant melanoma

“…-Suppression of BRAF (V600E) using different types of compounds that induce mitochondria reprograming has already shown considerable progress. In a unique recent approach triphenylo-phosphoniumconjugated nitroxide or ubiquinine was used to produce mitochondrial-membrane depolarization and subsequent oxidative stress (Hong et al, 2017). The results showed that PLX4032 resistant melanoma cells become sensitive in vitro and as well in murine SK-MEL28 xenografts without serious effects.…”

Nitroxides as Antioxidants and Anticancer Drugs

“…The studies conducted on the human melanoma cell lines (SK-MEL28, A375 and RPMI-7951) showed that Mito-CP effectively induced oxidative stress and in consequence depolarization of the mitochondrial membrane and apoptosis. Additionally, these tests exhibited a greater efficacy of nitroxide in comparison to a proto-oncogene BRAF inhibitor, Vemurafenib (PLX4032) [ 82 ].…”

Mitochondrial dysfunction and potential anticancer therapy

“…HIFs, which are degraded upon exposure to ROS, can be stabilized in hypoxic conditions and promote mitophagy . Autophagy‐mediated HIF2α degradation was shown to suppress renal tumorigenesis . The significance of metabolic reprogramming in mitochondria for maintenance of BRAF‐mutated melanomas and for development of their drug resistance to B‐Raf inhibitors has been reported …”

“…72 Autophagy-mediated HIF2 degradation was shown to suppress renal tumorigenesis. 76 The significance of metabolic reprogramming in mitochondria for maintenance of BRAF-mutated melanomas and for development of their drug resistance to B-Raf inhibitors has been reported. 77 MDF has strongly been linked to attenuation of apoptosis, and hence, increased cancer growth and progression.…”