Bedaquiline, an FDA-approved antibiotic, inhibits mitochondrial function and potently blocks the proliferative expansion of stem-like cancer cells (CSCs).
Bedaquiline, an FDA-approved antibiotic, inhibits mitochondrial function and potently blocks the proliferative expansion of stem-like cancer cells (CSCs).
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DOI：
10.18632/aging.100983
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发表时间：
2016-08
期刊：
影响因子：
--
通讯作者：
Lisanti MP
中科院分区：
文献类型：
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作者：
Fiorillo M;Lamb R;Tanowitz HB;Cappello AR;Martinez-Outschoorn UE;Sotgia F;Lisanti MP
贝达喹啉（又名，Sirturo）是一种抗微生物剂，FDA批准用于治疗耐多药肺结核（TB）。贝达喹啉是一类二芳基喹啉化合物，其机械地抑制细菌ATP合酶，并显示出对药物敏感性和耐药性TB的有效活性。有趣的是，真核线粒体最初是从吞噬的好氧细菌进化而来的。因此，我们假设，在哺乳动物细胞中，贝达喹啉也可能靶向线粒体ATP合酶，导致线粒体功能障碍和ATP耗竭。在这里，我们表明贝达喹啉具有抗癌活性，直接针对癌症干细胞样细胞（CSC）。更具体地说，我们证明贝达喹啉治疗MCF 7乳腺癌细胞抑制线粒体耗氧量，以及糖酵解，但诱导氧化应激。重要的是，贝达喹啉显著阻断MCF 7衍生的CSC的增殖和扩增，IC-50约为100。1 μM，使用乳腺微球测定法测定。同样，贝达喹啉也减少了在锚定非依赖性生长条件下的CD 44 +/CD 24低/− CSC和ALDH+ CSC群体。与此形成鲜明对比的是，贝达喹啉显著增加了正常人成纤维细胞的耗氧量，这与其在接受结核感染治疗的患者中耐受良好的事实一致。因此，未来可能需要在癌症患者中进行临床前研究和人体临床试验。有趣的是，我们还强调贝达喹啉与trans-piceatannol和trans-resveratrol具有某些结构相似性，trans-piceatannol和trans-resveratrol是已知的线粒体ATP合酶（复合物V）的天然类黄酮抑制剂，并显示出抗衰老特性。
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.