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dc.contributor.author
Verdura, Sara
dc.contributor.author
Cuyás, Elisabet
dc.contributor.author
Lozano Sánchez, Jesús
dc.contributor.author
Bastidas Velez, Cristian
dc.contributor.author
Llorach Parés, Laura
dc.contributor.author
Fernández Arroyo, Salvador
dc.contributor.author
Hernández Aguilera, Anna
dc.contributor.author
Joven, Jorge
dc.contributor.author
Nonell Canals, Alfons
dc.contributor.author
Bosch Barrera, Joaquim
dc.contributor.author
Martin Castillo, Begonã
dc.contributor.author
Vellón, Luciano
dc.contributor.author
Sanchez Martinez, Melchor
dc.contributor.author
Segura Carretero, Antonio
dc.contributor.author
Menendez, Javier A.
dc.date.available
2019-11-21T22:06:02Z
dc.date.issued
2019-03
dc.identifier.citation
Verdura, Sara; Cuyás, Elisabet; Lozano Sánchez, Jesús; Bastidas Velez, Cristian; Llorach Parés, Laura; et al.; An olive oil phenolic is a new chemotype of mutant isocitrate dehydrogenase 1 (IDH1) inhibitors; Oxford University Press; Carcinogenesis; 40; 1; 3-2019; 27-40
dc.identifier.issn
0143-3334
dc.identifier.uri
http://hdl.handle.net/11336/89504
dc.description.abstract
Mutations in the isocitrate dehydrogenase 1 (IDH1) gene confer an oncogenic gain-of-function activity that allows the conversion of α-ketoglutarate (α-KG) to the oncometabolite R-2-hydroxyglutarate (2HG). The accumulation of 2HG inhibits α-KG-dependent histone and DNA demethylases, thereby generating genome-wide hypermethylation phenotypes with cancer-initiating properties. Several chemotypes of mutant IDH1/2-targeted inhibitors have been reported, and some of them are under evaluation in clinical trials. However, the recognition of acquired resistance to such inhibitors within a few years of clinical use raises an urgent need to discover new mutant IDH1 antagonists. Here, we report that a naturally occurring phenolic compound in extra-virgin olive oil (EVOO) selectively inhibits the production of 2HG by neomorphic IDH1 mutations. In silico docking, molecular dynamics, including steered simulations, predicted the ability of the oleoside decarboxymethyl oleuropein aglycone (DOA) to preferentially occupy the allosteric pocket of mutant IDH1. DOA inhibited the enzymatic activity of recombinant mutant IDH1 (R132H) protein in the low micromolar range, whereas >10-fold higher concentrations were required to inhibit the activity of wild-type (WT) IDH1. DOA suppressed 2HG overproduction in engineered human cells expressing a heterozygous IDH1-R132H mutation. DOA restored the 2HG-suppressed activity of histone demethylases as it fully reversed the hypermethylation of H3K9me3 in IDH1-mutant cells. DOA epigenetically restored the expression of PD-L1, an immunosuppressive gene silenced in IDH1 mutant cells via 2HG-driven DNA hypermethylation. DOA selectively blocked colony formation of IDH1 mutant cells while sparing WT IDH1 isogenic counterparts. In sum, the EVOO-derived oleoside DOA is a new, naturally occurring chemotype of mutant IDH1 inhibitors.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Oxford University Press
dc.rights
info:eu-repo/semantics/restrictedAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
OLIVE OIL PHENOLIC
dc.subject
IDH1
dc.subject
BREAST CANCER
dc.subject
ONCOMETABOLYTE
dc.subject.classification
Bioquímica y Biología Molecular
dc.subject.classification
Ciencias Biológicas
dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
dc.title
An olive oil phenolic is a new chemotype of mutant isocitrate dehydrogenase 1 (IDH1) inhibitors
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2019-09-27T15:24:22Z
dc.journal.volume
40
dc.journal.number
1
dc.journal.pagination
27-40
dc.journal.pais
Reino Unido
dc.journal.ciudad
Oxford
dc.description.fil
Fil: Verdura, Sara. Parc Hospitalari Martí i Julià; España. Instituto Catalan de Oncología; España
dc.description.fil
Fil: Cuyás, Elisabet. Parc Hospitalari Martí i Julià; España. Instituto Catalan de Oncología; España
dc.description.fil
Fil: Lozano Sánchez, Jesús. Universidad de Granada; España. Centro de Investigación y Desarrollo del Alimento Funcional,; España
dc.description.fil
Fil: Bastidas Velez, Cristian. Parc Hospitalari Martí i Julià; España
dc.description.fil
Fil: Llorach Parés, Laura. Mind The Byte; España
dc.description.fil
Fil: Fernández Arroyo, Salvador. Universitat Rovira I Virgili; España
dc.description.fil
Fil: Hernández Aguilera, Anna. Universitat Rovira I Virgili; España
dc.description.fil
Fil: Joven, Jorge. Universitat Rovira I Virgili; España
dc.description.fil
Fil: Nonell Canals, Alfons. Mind The Byte; España
dc.description.fil
Fil: Bosch Barrera, Joaquim. Parc Hospitalari Martí i Julià; España. Universidad de Girona; España
dc.description.fil
Fil: Martin Castillo, Begonã. Universidad de Girona; España. Parc Hospitalari Martí i Julià; España
dc.description.fil
Fil: Vellón, Luciano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
dc.description.fil
Fil: Sanchez Martinez, Melchor. Mind The Byte; España
dc.description.fil
Fil: Segura Carretero, Antonio. Centro de Investigación y Desarrollo del Alimento Funcional,; España. Universidad de Granada; España
dc.description.fil
Fil: Menendez, Javier A.. Parc Hospitalari Martí i Julià; España. Instituto Catalan de Oncología; España
dc.journal.title
Carcinogenesis
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/carcin/article-abstract/40/1/27/5183298?redirectedFrom=fulltext
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1093/carcin/bgy159


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