Mitochondrial metabolism has emerged as a promising target against the mechanisms of tumor growth. Herein, we have screened an FDA-approved library to identify drugs that inhibit mitochondrial respiration. The β1-blocker nebivolol specifically hinders oxidative phosphorylation in cancer cells by concertedly inhibiting Complex I and ATP synthase activities. Complex I inhibition is mediated by interfering the phosphorylation of NDUFS7. Inhibition of the ATP synthase is exerted by the overexpression and binding of the ATPase Inhibitory Factor 1 (IF1) to the enzyme. Remarkably, nebivolol also arrests tumor angiogenesis by arresting endothelial cell proliferation. Altogether, targeting mitochondria and angiogenesis triggers a metabolic and oxidative stress crisis that restricts the growth of colon and breast carcinomas. Nebivolol holds great promise to be repurposed for the treatment of cancer patients.
Herein, we screen an FDA-approved library of small compounds to find drugs that could inhibit the activity of the mitochondrial ATP synthase in cancer cells and consequently could prevent tumor growth. We find 13 compounds that inhibit mitochondrial respiration and the activity of the ATP synthase. We study in detail the mechanisms by which the third-generation β1-blocker nebivolol halts colon and breast tumor growth in vivo. The results emphasize the relevance of blocking β1-adrenergic signaling to inhibit cancer progression, supporting the repurposing of nebivolol as an anticancer drug to be used in combined chemotherapy of the oncologic patient.