Paterson Institute, University of Manchester, Withington M20 4BX, United Kingdom; Translational Medicine, School of Environment and Life Sciences, Biomedical Research Centre (BRC), University of Salford, Greater Manchester M5 4WT, United Kingdom; The Department of Pharmacy, Health and Nutritional Sciences, The University of Calabria, Cosenza, Italy.
Paterson Institute, University of Manchester, Withington M20 4BX, United Kingdom.
Biochim Biophys Acta Bioenerg. 2018 Sep;1859(9):984-996. doi: 10.1016/j.bbabio.2018.03.018. Epub 2018 Apr 4.
Here, we show that a 2:1 mixture of Brutieridin and Melitidin, termed "BMF", has a statin-like properties, which blocks the action of the rate-limiting enzyme for mevalonate biosynthesis, namely HMGR (3-hydroxy-3-methylglutaryl-CoA-reductase). Moreover, our results indicate that BMF functionally inhibits several key characteristics of CSCs. More specifically, BMF effectively i) reduced ALDH activity, ii) blocked mammosphere formation and iii) inhibited the activation of CSC-associated signalling pathways (STAT1/3, Notch and Wnt/beta-catenin) targeting Rho-GDI-signalling. In addition, BMF metabolically inhibited mitochondrial respiration (OXPHOS) and fatty acid oxidation (FAO). Importantly, BMF did not show the same toxic side-effects in normal fibroblasts that were observed with statins. Lastly, we show that high expression of the mRNA species encoding HMGR is associated with poor clinical outcome in breast cancer patients, providing a potential companion diagnostic for BMF-directed personalized therapy.
在这里，我们表明，布屈替丁和米替丁的 2:1 混合物，称为“BMF”，具有他汀类药物的特性，可阻断甲羟戊酸生物合成的限速酶，即 HMGR（3-羟基-3-甲基戊二酰辅酶 A 还原酶）的作用。此外，我们的结果表明，BMF 可在功能上抑制 CSCs 的几个关键特征。更具体地说，BMF 有效地：i）降低 ALDH 活性，ii）阻断乳腺球体形成，iii）抑制与 Rho-GDI 信号相关的 CSC 相关信号通路（STAT1/3、Notch 和 Wnt/β-catenin）的激活。此外，BMF 代谢抑制线粒体呼吸（OXPHOS）和脂肪酸氧化（FAO）。重要的是，与他汀类药物在正常成纤维细胞中观察到的相同毒性副作用不同，BMF 并未在正常成纤维细胞中表现出相同的毒性副作用。最后，我们表明，HMGR 编码 mRNA 表达水平高与乳腺癌患者的临床预后不良相关，为 BMF 导向的个体化治疗提供了潜在的伴随诊断。
