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

Fiorillo, M, Lamb, R, Tanowitz, H, Cappello, A, Martinez‐Outschoorn, U, Sotgia, Federica ORCID: https://orcid.org/0000-0003-2826-4529 and Lisanti, MP ORCID: https://orcid.org/0000-0003-2034-1382 2016, 'Bedaquiline, an FDA-approved antibiotic, inhibits mitochondrial function and potently blocks the proliferative expansion of stem-like cancer cells (CSCs)' , Aging, 8 (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 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.

Item Type:	Article
Schools:	Schools > School of Environment and Life Sciences > Biomedical Research Centre
Journal or Publication Title:	Aging
Publisher:	Impact Journals
Related URLs:	Publication
Funders:	Heritage Lottery Fund
Depositing User:	F Sotgia
Date Deposited:	29 Jun 2016 07:39
Last Modified:	30 Jul 2020 08:15
URI:	http://usir.salford.ac.uk/id/eprint/39196

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