Bedaquiline, an FDA-approved antibiotic, inhibits mitochondrial function and potently blocks the proliferative expansion of stem-like cancer cells (CSCs)

Marco Fiorillo, Rebecca Lamb, Herbert B. Tanowitz, Anna Rita Cappello, Ubaldo E. Martinez-Outschoorn, Federica Sotgia, Michael P. Lisanti

Research output: Contribution to journalArticle

41 Citations (Scopus)

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 oxygenconsumption, 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 anchorageindependent 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.

Original languageEnglish (US)
Pages (from-to)1593-1607
Number of pages15
JournalAging
Volume8
Issue number8
DOIs
StatePublished - 2016

Fingerprint

bedaquiline
Neoplastic Stem Cells
Anti-Bacterial Agents
Mitochondrial Proton-Translocating ATPases
Multidrug-Resistant Tuberculosis
Adenosine Triphosphate
Aerobic Bacteria
Glycolysis
Anti-Infective Agents
Pulmonary Tuberculosis
Flavonoids
Oxygen Consumption

Keywords

  • Bedaquiline
  • Cancer stem-like cells (CSCs)
  • Drug repurposing
  • Mitochondria
  • Tumor-initiating cells (TICs)

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

Fiorillo, M., Lamb, R., Tanowitz, H. B., Cappello, A. R., Martinez-Outschoorn, U. E., Sotgia, F., & Lisanti, M. P. (2016). Bedaquiline, an FDA-approved antibiotic, inhibits mitochondrial function and potently blocks the proliferative expansion of stem-like cancer cells (CSCs). Aging, 8(8), 1593-1607. https://doi.org/10.18632/aging.100983

Bedaquiline, an FDA-approved antibiotic, inhibits mitochondrial function and potently blocks the proliferative expansion of stem-like cancer cells (CSCs). / Fiorillo, Marco; Lamb, Rebecca; Tanowitz, Herbert B.; Cappello, Anna Rita; Martinez-Outschoorn, Ubaldo E.; Sotgia, Federica; Lisanti, Michael P.

In: Aging, Vol. 8, No. 8, 2016, p. 1593-1607.

Research output: Contribution to journalArticle

Fiorillo, M, Lamb, R, Tanowitz, HB, Cappello, AR, Martinez-Outschoorn, UE, Sotgia, F & Lisanti, MP 2016, 'Bedaquiline, an FDA-approved antibiotic, inhibits mitochondrial function and potently blocks the proliferative expansion of stem-like cancer cells (CSCs)', Aging, vol. 8, no. 8, pp. 1593-1607. https://doi.org/10.18632/aging.100983
Fiorillo, Marco ; Lamb, Rebecca ; Tanowitz, Herbert B. ; Cappello, Anna Rita ; Martinez-Outschoorn, Ubaldo E. ; Sotgia, Federica ; Lisanti, Michael P. / Bedaquiline, an FDA-approved antibiotic, inhibits mitochondrial function and potently blocks the proliferative expansion of stem-like cancer cells (CSCs). In: Aging. 2016 ; Vol. 8, No. 8. pp. 1593-1607.
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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 oxygenconsumption, 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 anchorageindependent 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.",
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