@misc{10481/51214,
year = {2018},
month = {2},
url = {http://hdl.handle.net/10481/51214},
abstract = {Targeting tumor-initiating, drug-resistant populations of cancer stem cells (CSC) with phytochemicals is a novel
paradigm for cancer prevention and treatment. We herein employed a phenotypic drug discovery approach coupled to
mechanism-of-action profiling and target deconvolution to identify phenolic components of extra virgin olive oil (EVOO)
capable of suppressing the functional traits of CSC in breast cancer (BC). In vitro screening revealed that the secoiridoid
decarboxymethyl oleuropein aglycone (DOA) could selectively target subpopulations of epithelial-like, aldehyde
dehydrogenase (ALDH)-positive and mesenchymal-like, CD44+CD24−/low CSC. DOA could potently block the formation of
multicellular tumorspheres generated from single-founder stem-like cells in a panel of genetically diverse BC models.
Pretreatment of BC populations with noncytotoxic doses of DOA dramatically reduced subsequent tumor-forming capacity
in vivo. Mice orthotopically injected with CSC-enriched BC-cell populations pretreated with DOA remained tumor-free for
several months. Phenotype microarray-based screening pointed to a synergistic interaction of DOA with the mTOR inhibitor
rapamycin and the DNA methyltransferase (DNMT) inhibitor 5-azacytidine. In silico computational studies indicated that
DOA binds and inhibits the ATP-binding kinase domain site of mTOR and the S-adenosyl-l-methionine (SAM) cofactorbinding
pocket of DNMTs. FRET-based Z-LYTE™ and AlphaScreen-based in vitro assays confirmed the ability of DOA to
function as an ATP-competitive mTOR inhibitor and to block the SAM-dependent methylation activity of DNMTs. Our
systematic in vitro, in vivo and in silico approaches establish the phenol-conjugated oleoside DOA as a dual mTOR/DNMT
inhibitor naturally occurring in EVOO that functionally suppresses CSC-like states responsible for maintaining tumorinitiating
cell properties within BC populations.},
organization = {This work was supported by grants from the Ministerio de
Ciencia e Innovación (Grant SAF2016-80639-P to J.A.M.),
Plan Nacional de I+D+I, Spain, the Agència de Gestió d’Ajuts
Universitaris i de Recerca (AGAUR; Grant 2014 SGR229 to J.A.M.),
Departament d’Economia i Coneixement, Catalonia, Spain,
the Andalusian Regional Government Council of Innovation
and Science (Grant P11-CTS-7625 to A.S.-C.), the Ministerio de
Economía, Industria y Competitividad, Spain (Grants AGL2015-
67995-C2-3-R and AGL2015-67995-C3-1-R to A.S.-C. and V.M.)
and Conselleria d’Educació, Investigació, Cultura I Esport,
Generalitat Valenciana, Spain (Grant PROMETEO/2016/006 to
V.M). E.C. is supported by the Sara Borrell post doctoral contract
(CD15/00033) from the Ministerio de Sanidad y Consumo,
Fondo de Investigación Sanitaria (FIS), Spain.},
publisher = {Oxford University Press},
title = {Extra-virgin olive oil contains a metabolo-epigenetic inhibitor of cancer stem cells},
doi = {10.1093/carcin/bgy023},
author = {Lozano Sánchez, Jesús and Corominas-Faja, Bruna and Cuyàs, Elisabet and Cufí, Sílvia and Verdura, Sara and Fernández-Arroyo, Salvador and Borras Linares, María Isabel and Martin-Castillo, Begoña and Martin, Ángel G. and Lupu, Ruth and Nonell-Canals, Alfons and Sanchez-Martinez, Melchor and Micol Molina, Vicente and Joven, Jorge and Segura Carretero, Antonio and Menendez, Javier A.},
}