Abstract
The extra virgin olive oil (EVOO) dihydroxy-phenol oleacein is a natural inhibitor of multiple metabolic and epigenetic enzymes capable of suppressing the functional traits of cancer stem cells (CSC). Here, we used a natural product-inspired drug discovery approach to identify new compounds that phenotypically mimic the anti-CSC activity of oleacein. We coupled 3D quantitative structure-activity relationship-based virtual profiling with phenotypic analysis using 3D tumorsphere formation as a gold standard for assessing the presence of CSC. Among the top 20 computationally-predicted oleacein mimetics, four fulfilled the phenotypic endpoint of specifically suppressing the tumorsphere-initiating capacity of CSC, in the absence of significant cytotoxicity against differentiated cancer cells growing in 2D cultures in the same low micromolar concentration range. Of these, 3,4-dihydrophenetyl butyrate –a lipophilic ester conjugate of the hydroxytyrosol moiety of oleacein– and (E)-N-allyl-2-((5-nitrofuran-2-yl)methylene)hydrazinecarbothioamide) –an inhibitor of Trypanosoma cruzi triosephosphate isomerase– were also highly effective at significantly reducing the proportion of aldehyde dehydrogenase (ALDH)-positive CSC-like proliferating cells. Preservation of the mTOR/DNMT binding mode of oleacein was dispensable for suppression of the ALDH+-CSC functional phenotype in hydroxytyrosol-unrelated mimetics. The anti-CSC chemistry of complex EVOO phenols such as oleacein can be phenocopied through the use of mimetics capturing its physico-chemical properties.
Highlights
Extra virgin olive oil (EVOO) is a unique functional food with a major contribution to the health-promoting effects of the so-called Mediterranean diet
Using a holistic approach for phenotypic drug discovery coupled with mechanism-of-action functional profiling and target deconvolution, we recently identified the dihydroxy-phenol oleacein [11,12,13,14,15,16,17] as a metabolo-epigenetic inhibitor of the mammalian target of rapamycin kinase and DNA methyltransferases (DNMTs)
We in silico compared the binding modes of the top 20 computationally-predicted oleacein mimetics to the two molecular targets originally involved in the capacity of oleacein to suppress the functional traits of tumor-initiating cancer stem cells (CSC) [14]
Summary
Extra virgin olive oil (EVOO) is a unique functional food with a major contribution to the health-promoting effects of the so-called Mediterranean diet. Using a holistic approach for phenotypic drug discovery coupled with mechanism-of-action functional profiling and target deconvolution, we recently identified the dihydroxy-phenol oleacein (the dialdehydic form of decarboxymethyl elenolic acid linked to hydroxytyrosol) [11,12,13,14,15,16,17] as a metabolo-epigenetic inhibitor of the mammalian target of rapamycin (mTOR) kinase and DNA methyltransferases (DNMTs). The anti-CSC effects of oleacein are most likely related to its chemical structure, largely due to the presence of two hydroxyl groups in the hydroxytyrosol moiety [9, 19,20,21]. One could envision that its scaffold might be used as a chemical prototype to facilitate selection and advancement of new anti-CSC hits via cell-based phenotypic screenings. The ability of oleacein to operate as a multi-faceted regulator of numerous metabolic processes and chromatin-modifying enzymatic activities might open new horizons for CSCtargeted therapy based on the molecular bridge that connects metabolism and epigenetics with the aberrant state of stemness in cancer tissues [23,24,25,26,27,28], a biomimicry design process of oleacein mimetics remains a highly challenging task
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