Directed phenotype switching as an effective antimelanoma strategy

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-associate...

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Bibliographic Details
Published in:Cancer cell Vol. 24; no. 1; p. 105
Main Authors: Sáez-Ayala, Magalí, Montenegro, María F, Sánchez-Del-Campo, Luis, Fernández-Pérez, María Piedad, Chazarra, Soledad, Freter, Rasmus, Middleton, Mark, Piñero-Madrona, Antonio, Cabezas-Herrera, Juan, Goding, Colin R, Rodríguez-López, José Neptuno
Format: Journal Article
Language:English
Published: United States 08.07.2013
Subjects:
Apoptosis - drug effects
Catechin - analogs & derivatives
Catechin - pharmacology
Cell Differentiation - drug effects
Cell Line, Tumor
DNA Damage
E2F1 Transcription Factor - physiology
Humans
Melanoma - drug therapy
Melanoma - pathology
Methotrexate - pharmacology
Microphthalmia-Associated Transcription Factor - genetics
Phenotype
Thymine Nucleotides - metabolism
ISSN:1878-3686, 1878-3686
Online Access:Get more information
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Summary: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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ISSN:1878-3686
1878-3686
DOI:10.1016/j.ccr.2013.05.009