Journal
AGING-US
Volume 12, Issue 21, Pages 21057-21075Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/aging.202154
Keywords
olive oil; mTOR; DNMT; metabolism; epigenetics
Categories
Funding
- Spanish Ministry of Science and Innovation [SAF2016-80639-P, PID2019-104055GB-I00]
- Fundacio Oncolliga Girona (Lliga catalana d'ajuda al malalt de cancer, Girona)
- La Marato de TV3 foundation [201906]
- Health Research and Innovation Strategic Plan (PERIS 2016-2020
- Pla strategic de recerca i innovacio en salut
- Departament de Salut, Generalitat de Catalunya) [SLT006/17/114]
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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
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