Directed Phenotype Switching as an Effective Antimelanoma Strategy

• Published in: Cancer cell Vol. 24; no. 1; pp. 105 - 119
• 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 Elsevier Inc 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: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccr.2013.05.009

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. •Methotrexate eradicates invasive melanoma cells via upregulation of MITF•Methotrexate-mediated phenotype switching promotes tyrosinase expression•A tyrosinase-activated prodrug TMECG kills melanoma cells by dTTP depletion•Methotrexate/TMECG induces apoptosis in melanoma irrespective of BRAF or p53 status