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.
Highlights
Numerous studies have demonstrated that functional mitochondria are required for tumorigenesis, suggesting that mitochondrial oxidative phosphorylation (OXPHOS) might be a potential target for cancer therapy
We demonstrate that BAY 87-2243-mediated complex I inhibition induced significant reduction of cell viability in a dose-dependent manner in several BRAFV600E (G-361, SK-MEL-5, SK-MEL-28, and A-375) and BRAF wild type (SK-MEL-2, IPC-298, CHL-1, and Colo-792) melanoma cell lines
To address whether BAY 87-2243-mediated complex I inhibition is efficient at reducing melanoma tumor growth in vivo, we tested the inhibitor in four BRAF mutant melanoma xenograft models using G-361, SK-MEL28, A-375, and LOX-IMVI cancer cells
Summary
Numerous studies have demonstrated that functional mitochondria are required for tumorigenesis, suggesting that mitochondrial oxidative phosphorylation (OXPHOS) might be a potential target for cancer therapy. Cancer cells require mitochondrial oxidative metabolism to maintain their redox balance. When ROS production exceeds the capacity of intracellular ROS-detoxifying systems, cell-toxic oxidative stress is induced. This explains why cancer cells have to tightly control the balance between ROS generation and scavenging in order to remain within the pro-tumorigenic range of ROS levels [13]. In this sense, cancer cells display an increased ROS scavenging capacity that prevents ROS levels from reaching cytotoxic levels incompatible with growth [14, 15]
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