title: Bedaquiline, an FDA-approved antibiotic, inhibits mitochondrial function and potently blocks the proliferative expansion of stem-like cancer cells (CSCs).
abstract: Bedaquiline (a.k.a., Sirturo) is an anti-microbial agent, which is approved by the FDA for the treatment of multi-drug resistant pulmonary tuberculosis (TB). Bedaquiline is a first-in-class diaryl-quinoline compound, that mechanistically inhibits the bacterial ATP-synthase, and shows potent activity against both drug-sensitive and drug-resistant TB. Interestingly, eukaryotic mitochondria originally evolved from engulfed aerobic bacteria. Thus, we hypothesized that, in mammalian cells, bedaquiline might also target the mitochondrial ATP-synthase, leading to mitochondrial dysfunction and ATP depletion. Here, we show that bedaquiline has anti-cancer activity, directed against Cancer Stem-like Cells (CSCs). More specifically, we demonstrate that bedaquiline treatment of MCF7 breast cancer cells inhibits mitochondrial oxygen-consumption, as well as glycolysis, but induces oxidative stress. Importantly, bedaquiline significantly blocks the propagation and expansion of MCF7-derived CSCs, with an IC-50 of approx. 1-μM, as determined using the mammosphere assay. Similarly, bedaquiline also reduces both the CD44+/CD24low/- CSC and ALDH+ CSC populations, under anchorage-independent growth conditions. In striking contrast, bedaquiline significantly increases oxygen consumption in normal human fibroblasts, consistent with the fact that it is well-tolerated in patients treated for TB infections. As such, future pre-clinical studies and human clinical trials in cancer patients may be warranted. Interestingly, we also highlight that bedaquiline shares certain structural similarities with trans-piceatannol and trans-resveratrol, which are known natural flavonoid inhibitors of the mitochondrial ATP-synthase (complex V) and show anti-aging properties.
authors.affiliation: The Breast Cancer Now Research Unit, Institute of Cancer Sciences, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.|The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.|The Department of Pharmacy, Health and Nutritional Sciences, The University of Calabria, Cosenza, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Fiorillo
authors.affiliation: The Breast Cancer Now Research Unit, Institute of Cancer Sciences, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.|The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Lamb
authors.affiliation: Departments of Pathology and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Tanowitz
authors.affiliation: The Department of Pharmacy, Health and Nutritional Sciences, The University of Calabria, Cosenza, Italy.
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Cappello
authors.affiliation: The Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA.
authors.forename: Ubaldo E
authors.initials: UE
authors.lastname: Martinez-Outschoorn
authors.affiliation: School of Environment and Life Sciences, University of Salford, Salford, UK.
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
authors.affiliation: The Breast Cancer Now Research Unit, Institute of Cancer Sciences, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.|The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D064687:Diarylquinolines / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects
chemical_list: D000995:Antitubercular Agents; D064687:Diarylquinolines; C493870:bedaquiline
keywords: bedaquiline; cancer stem-like cells (CSCs); drug repurposing; mitochondria; tumor-initiating cells (TICs)