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

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.

Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition

“…These findings are in agreement with our previous observation in mouse heart mitochondria using a pharmacological approach [ 28 ]. Consistently, IF1 co-purifies with and is bound to the tetrameric ATP synthase in porcine and ovine heart mitochondria [ 26 , 27 ] and with monomers and dimers of the enzyme in other mouse tissues [ 30 ] and in human cell lines [ 54 ].…”

Specific Effects of Trabectedin and Lurbinectedin on Human Macrophage Function and Fate—Novel Insights

“…Seahorse analyser was calibrated with a calibrating Seahorse XF solution (Agilent, 103059-000). Respiratory chain inhibitors were used at these concentrations: 6 μM oligomycin, 0.75 mM DNP (2′,4′-dinitrophenol), 1 μM rotenone, and 1 μM antimycin A [ 64 ].…”

An optimized protocol for coupling oxygen consumption rates with β-oxidation in isolated mitochondria from mouse soleus

“… Note: This and other protocols require coupled mitochondria ( Nuevo-Tapioles et al., 2020 ). When coupling is not required (ETC enzymatic activities, blue native, in-gel activities among others protocols ( Nuevo-Tapioles et al., 2020 )) h and i steps may be repeated once or twice to enhance mitochondrial purity. CRITICAL: Buffer B may interfere with protein measurement.…”

“… Eliminate gas bubbles in the proximity of the Teflon membrane ( Figure 2 ) Consider increasing the concentration of mitochondrial protein in the chamber. Mitochondrial activity decreases with aging ( Kauppila et al., 2017 ) or pathologies ( Balaban et al., 2005 ; Dillin et al., 2002 ; Formentini et al., 2012 ; Formentini et al., 2017b ; Nuevo-Tapioles et al., 2020 ) …”