Directed phenotype switching as an effective antimelanoma strategy.

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.

journal_name

Cancer Cell

journal_title

Cancer cell

authors

Sáez-Ayala M,Montenegro MF,Sánchez-Del-Campo L,Fernández-Pérez MP,Chazarra S,Freter R,Middleton M,Piñero-Madrona A,Cabezas-Herrera J,Goding CR,Rodríguez-López JN

doi

10.1016/j.ccr.2013.05.009

subject

Has Abstract

pub_date

2013-07-08 00:00:00

pages

105-19

issue

1

eissn

1535-6108

issn

1878-3686

pii

S1535-6108(13)00236-5

journal_volume

24

pub_type

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