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

Abstract

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.

• Authors: Marco Fiorillo, Maria Peiris-Pagès, Rosa Sanchez-Alvarez, Lucia Bartella, Leonardo Di Donna, Vincenza Dolce, Giovanni Sindona, Federica Sotgia, Anna Rita Cappello, Michael P Lisanti
• Journal: Biochimica et biophysica acta. Bioenergetics (Biochim Biophys Acta Bioenerg) Vol. 1859 Issue 9 Pg. 984-996 (09 2018) ISSN: 0005-2728 [Print] Netherlands
• PMID: 29626418 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Biological Products
• Biomarkers, Tumor
• Plant Oils
• rho-Specific Guanine Nucleotide Dissociation Inhibitors
• bergamot oil
• Hydroxymethylglutaryl CoA Reductases
• Mevalonic Acid

Topics

• Apoptosis (drug effects)
• Biological Products (pharmacology)
• Biomarkers, Tumor (metabolism)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Female
• Fibroblasts (cytology, drug effects, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hydroxymethylglutaryl CoA Reductases (metabolism)
• Mevalonic Acid (metabolism)
• Mitochondria (drug effects, metabolism, pathology)
• Neoplasm Metastasis
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Plant Oils (chemistry)
• Prognosis
• Signal Transduction (drug effects)
• Survival Rate
• rho-Specific Guanine Nucleotide Dissociation Inhibitors (metabolism)