Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
Oncol Rep. 2018 Jun;39(6):3041-3047. doi: 10.3892/or.2018.6337. Epub 2018 Mar 27.
Targeting cancer stem cells (CSCs) is a key strategy to prevent cancers from developing drug resistance and metastasis. Mitochondria have been reported to be a vulnerability of CSCs by multiple studies. Here, we report that doxycycline, functioning as an inhibitor of mitochondrial biogenesis, can effectively target breast cancer stem cells (BCSCs). Our results revealed that doxycycline significantly decreased the frequency of aldehyde dehydrogenase‑positive (ALDH+) BCSCs as well as mammosphere formation efficiency in HER2+ and triple‑negative breast cancer (TNBC) subtypes. Doxycycline also ameliorated paclitaxel‑induced enrichment of ALDH+ BCSCs in TNBC. Mechanistically, we showed that doxycycline decreased the level of reactive oxygen species and their downstream p38 MAPK pathway. In agreement with the key role for p38 in maintaining BCSCs, a specific inhibitor targeting this MAPK pathway significantly decreased the number of ALDH+ cells. Doxycycline is a FDA‑approved drug with minor and limited side‑effects. Given doxycycline's low toxicity and strong effect on BCSC inhibition, we report that doxycycline should be safe to be used concomitantly with chemotherapy drugs to eradicate both CSCs and bulk tumor cells.
靶向肿瘤干细胞（CSCs）是防止癌症产生耐药性和转移的关键策略。多项研究表明，线粒体是 CSCs 的一个脆弱靶点。在这里，我们报告多西环素作为线粒体生物发生的抑制剂，可有效靶向乳腺癌干细胞（BCSCs）。我们的结果表明，多西环素显著降低了 HER2+和三阴性乳腺癌（TNBC）亚型中醛脱氢酶阳性（ALDH+）BCSCs 的频率以及类乳腺球体形成效率。多西环素还改善了紫杉醇诱导的 TNBC 中 ALDH+BCSCs 的富集。在机制上，我们表明多西环素降低了活性氧水平及其下游 p38 MAPK 途径。与 p38 在维持 BCSCs 中的关键作用一致，针对该 MAPK 途径的特异性抑制剂显著减少了 ALDH+细胞的数量。多西环素是一种 FDA 批准的药物，副作用小且有限。鉴于多西环素的低毒性和对 BCSC 抑制作用的强大效果，我们报告说，多西环素与化疗药物联合使用应该是安全的，可以同时消除 CSCs 和肿瘤细胞。
