Targeting mitochondrial complex I using BAY 87-2243 reduces melanoma tumor growth
Background: Numerous studies have shown that functional mitochondria are essential for tumorigenesis, suggesting that mitochondrial oxidative phosphorylation (OXPHOS) could be a promising target for cancer therapy. In this study, we examined the effects of BAY 87-2243, a small molecule that inhibits complex I, the first enzyme in the OXPHOS pathway, on melanoma in both in vitro and in vivo models.
Results: BAY 87-2243 reduced mitochondrial oxygen consumption and caused partial depolarization of the mitochondrial membrane potential. This was accompanied by increased levels of reactive oxygen species (ROS), decreased total cellular ATP, activation of AMP-activated protein kinase (AMPK), and reduced cell viability. The loss of cell viability could be rescued by the antioxidant vitamin E or by increasing extracellular glucose levels (25 mM), suggesting that ROS-induced cell death and a shift toward glycolysis for survival were key mechanisms in response to BAY 87-2243. In vivo, BAY 87-2243 significantly inhibited tumor growth in several BRAF mutant melanoma mouse xenograft and patient-derived melanoma models. Additionally, we found that inhibiting mutated BRAF with the small molecule vemurafenib increased OXPHOS dependency in BRAF mutant melanoma cells, and combining both BAY 87-2243 and vemurafenib enhanced the anti-tumor effect in BRAF mutant melanoma mouse xenografts.
Conclusions: Our findings suggest that inhibiting complex I with BAY 87-2243 could have clinical applications as a monotherapy in melanoma and may also be effective in combination with BRAF inhibitors for treating patients with BRAF mutant melanoma.