Publication: Directed Phenotype Switching as an Effective Antimelanoma Strategy
Authors
Sáez Ayala, Magalí ; Fernández Pérez, María Piedad ; Chazarra Parres, Soledad ; Freter, Rasmus ; Middleton, Mark ; Piñero Madrona, Antonio ; Cabezas Herrera, Juan ; Goding, Colin R. ; Montenegro Arce, María Fernanda ; Rodríguez López, José Neptuno ; Sánchez del Campo Ferrer, Luis
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Publisher
Cell Press
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DOI
https://doi.org/10.1016/j.ccr.2013.05.009
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info:eu-repo/semantics/article
Description
©2013 Elsevier Inc. This document is the Published Manuscript version of a Published Work that
appeared in final form in Cancer cell. To access the final edited and published work see https://doi.org/10.1016/j.ccr.2013.05.009
Abstract
Therapeutic resistance in melanoma and other cancers arises via irreversible genetic, and dynamic phenotypic, heterogeneity. Here, we use directed phenotype switching in melanoma to sensitize melanoma cells to lineage-specific therapy. We show that methotrexate (MTX) induces microphthalmia-associated transcription factor (MITF) expression to inhibit invasiveness and promote differentiation-associated expression of the melanocyte-specific Tyrosinase gene. Consequently, MTX sensitizes melanomas to a tyrosinase-processed antifolate prodrug 3-O-(3,4,5-trimethoxybenzoyl)-(−)-epicatechin (TMECG), that inhibits the essential enzyme DHFR with high affinity. The combination of MTX and TMECG leads to depletion of thymidine pools, double-strand DNA breaks, and highly efficient E2F1-mediated apoptosis in culture and in vivo. Importantly, this drug combination delivers an effective and tissue-restricted antimelanoma therapy in vitro and in vivo irrespective of BRAF, MEK, or p53 status.
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Citation
Cancer Cell, volumen 24, número 1, año 2013
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1-ene-2999
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