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.

Mitochondrial “power” drives tamoxifen resistance: NQO1 and GCLC are new therapeutic targets in breast cancer

“…In direct support of our hypothesis, TAMR cells showed a significant increase in both mitochondrial mass and mitochondrial membrane potential (Figure 5), as observed by FACS analysis using MitoTracker vital dyes as probes (Deep Red and Orange) [19, 20]. However, this phenotype was strictly dependent on the presence of tamoxifen in the tissue culture media.…”

Targeting Cancer Stem Cells with Small Molecules

“…Furthermore, it selectively targets CD44 high /CD24 low CSCs. [70] Taken together, these studies open up unanticipated opportunities for therapeutic intervention.…”

Membrane plasticity facilitates recognition of the inhibitor oligomycin by the mitochondrial ATP synthase rotor

“…Oligomycin and apoptolidin, for example, inhibit the mitochondrial ATP synthase but not the bacterial enzymes, and have been reported to have anti-cancer activity [20–22]. By contrast, the compound known as bedaquiline, FDA-approved as Sirturo, has been reported to selectively target mycobacterial enzymes, including that of M. tuberculosis [23–26], although evidence of mitochondrial function inhibition [27] suggest this drug might be less selective than originally thought.…”