Bergamot natural products eradicate cancer stem cells (CSCs) by targeting mevalonate, Rho-GDI-signalling and mitochondrial metabolism

Here, we show that a 2:1 mixture of Brutieridin and Melitidin, termed “BMF”, has a statin-like properties, which\ud blocks the action of the rate-limiting enzyme for mevalonate biosynthesis, namely HMGR (3-hydroxy-3-methylglutaryl-\ud CoA-reductase). Moreover, our results indicate that BMF functionally inhibits several key characteristics\ud of CSCs. More specifically, BMF effectively i) reduced ALDH activity, ii) blocked mammosphere\ud formation and iii) inhibited the activation of CSC-associated signalling pathways (STAT1/3, Notch and Wnt/\ud beta-catenin) targeting Rho-GDI-signalling. In addition, BMF metabolically inhibited mitochondrial respiration\ud (OXPHOS) and fatty acid oxidation (FAO). Importantly, BMF did not show the same toxic side-effects in normal\ud fibroblasts that were observed with statins. Lastly, we show that high expression of the mRNA species encoding\ud HMGR is associated with poor clinical outcome in breast cancer patients, providing a potential companion\ud diagnostic for BMF-directed personalized therapy.