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Mimetics of extra virgin olive oil phenols with anti-cancer stem cell activity.
- Source :
-
Aging [Aging (Albany NY)] 2020 Nov 09; Vol. 12 (21), pp. 21057-21075. Date of Electronic Publication: 2020 Nov 09. - Publication Year :
- 2020
-
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 <superscript>+</superscript> -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.
- Subjects :
- Breast Neoplasms drug therapy
Cell Line, Tumor
DNA (Cytosine-5-)-Methyltransferases antagonists & inhibitors
DNA Methyltransferase 3A
Drug Discovery
Humans
TOR Serine-Threonine Kinases antagonists & inhibitors
Antineoplastic Agents administration & dosage
Antineoplastic Agents chemical synthesis
Biomimetic Materials administration & dosage
Biomimetic Materials chemical synthesis
Neoplastic Stem Cells drug effects
Olive Oil chemistry
Phenols chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1945-4589
- Volume :
- 12
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Aging
- Publication Type :
- Academic Journal
- Accession number :
- 33168787
- Full Text :
- https://doi.org/10.18632/aging.202154