Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATPase Inhibitory Protein
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Adrenergic Antagonists / pharmacology*
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Angiogenesis Inducing Agents / pharmacology*
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / physiopathology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Colonic Neoplasms / drug therapy
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Colonic Neoplasms / genetics
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Colonic Neoplasms / metabolism*
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Colonic Neoplasms / physiopathology*
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Female
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Humans
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Male
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Mitochondria / drug effects*
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Mitochondria / genetics
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Mitochondria / metabolism
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Mitochondrial Proton-Translocating ATPases / genetics
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Mitochondrial Proton-Translocating ATPases / metabolism
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NADH Dehydrogenase / genetics
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NADH Dehydrogenase / metabolism
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Nebivolol / pharmacology*
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Oxidative Phosphorylation / drug effects
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Proteins / genetics
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Proteins / metabolism
Substances
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Adrenergic Antagonists
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Angiogenesis Inducing Agents
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Proteins
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Nebivolol
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NADH Dehydrogenase
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Mitochondrial Proton-Translocating ATPases
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NDUFS7 protein, human