Coordinate β-adrenergic inhibition of mitochondrial activity and angiogenesis arrest tumor growth

Nat Commun. 2020 Jul 17;11(1):3606. doi: 10.1038/s41467-020-17384-1.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Antagonists / pharmacology*
  • Angiogenesis Inducing Agents / pharmacology*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / physiopathology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / physiopathology*
  • Female
  • Humans
  • Male
  • Mitochondria / drug effects*
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondrial Proton-Translocating ATPases / genetics
  • Mitochondrial Proton-Translocating ATPases / metabolism
  • NADH Dehydrogenase / genetics
  • NADH Dehydrogenase / metabolism
  • Nebivolol / pharmacology*
  • Oxidative Phosphorylation / drug effects
  • Proteins / genetics
  • Proteins / metabolism

Substances

  • ATPase inhibitory protein
  • Adrenergic Antagonists
  • Angiogenesis Inducing Agents
  • Proteins
  • Nebivolol
  • NADH Dehydrogenase
  • Mitochondrial Proton-Translocating ATPases
  • NDUFS7 protein, human