Targeting mitochondrial complex I using BAY 87-2243 reduces melanoma tumor growth

Abstract

BackgroundNumerous studies have demonstrated that functional mitochondria are required for tumorigenesis, suggesting that mitochondrial oxidative phosphorylation (OXPHOS) might be a potential target for cancer therapy. In this study, we investigated the effects of BAY 87-2243, a small molecule that inhibits the first OXPHOS enzyme (complex I), in melanoma in vitro and in vivo.ResultsBAY 87-2243 decreased mitochondrial oxygen consumption and induced partial depolarization of the mitochondrial membrane potential. This was associated with increased reactive oxygen species (ROS) levels, lowering of total cellular ATP levels, activation of AMP-activated protein kinase (AMPK), and reduced cell viability. The latter was rescued by the antioxidant vitamin E and high extracellular glucose levels (25 mM), indicating the involvement of ROS-induced cell death and a dependence on glycolysis for cell survival upon BAY 87-2243 treatment. BAY 87-2243 significantly reduced tumor growth in various BRAF mutant melanoma mouse xenografts and patient-derived melanoma mouse models. Furthermore, we provide evidence that inhibition of mutated BRAF using the specific small molecule inhibitor vemurafenib increased the OXPHOS dependency of BRAF mutant melanoma cells. As a consequence, the combination of both inhibitors augmented the anti-tumor effect of BAY 87-2243 in a BRAF mutant melanoma mouse xenograft model.ConclusionsTaken together, our results suggest that complex I inhibition has potential clinical applications as a single agent in melanoma and also might be efficacious in combination with BRAF inhibitors in the treatment of patients with BRAF mutant melanoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s40170-015-0138-0) contains supplementary material, which is available to authorized users.

Targeting Metabolism for Cancer Therapy

“…Although the precise mechanism of metformin action remains controversial (Luengo et al, 2014), recent work has shown that the anti-tumorigenic effect of metformin can at least be partially accounted for by direct mitochondrial complex I inhibition in tumors (Gui et al, 2016; Wheaton et al, 2014). Consistent with this notion, other complex I inhibitors have shown efficacy as anti-tumor agents (Appleyard et al, 2012; Schockel et al, 2015) and may show selective toxicity against oncogene-ablation resistant cells (Viale et al, 2014) and cancer stem cells (Sancho et al, 2015). Additional complex I inhibitors are under development (Bastian et al, 2017), and other inhibitors of respiration or mitochondrial metabolism, including the lipoic acid derivative CPI-613 (Table 1), are currently being assessed in clinical trials (Lycan et al, 2016; Pardee et al, 2014).…”

Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin

“…Additionally, other complex I inhibitors have shown efficacy as anti-tumor agents (Schockel et al, 2015; Zhang et al, 2014). Together these data support the hypothesis that tumor autonomous inhibition of complex I and respiration play an important role in the anti-tumorigenic effect of metformin.…”

AG311, a small molecule inhibitor of complex I and hypoxia-induced HIF-1α stabilization

“…For example, the anti-diabetic biguanides metformin and phenformin have been shown to exert their anticancer effect by inhibiting complex I, the first enzyme in the mitochondrial electron transport chain (ETC) [5–8]. BAY-87-2243, another complex I inhibitor, has shown efficacy in a preclinical model of resistant melanoma [9]. The small molecule, IACS-10759, was specifically designed as a complex I inhibitor to target chemoresistant dormant tumors [9,10].…”