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 Celljournal_title
Cancer cellauthors
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 JNdoi
10.1016/j.ccr.2013.05.009subject
Has Abstractpub_date
2013-07-08 00:00:00pages
105-19issue
1eissn
1535-6108issn
1878-3686pii
S1535-6108(13)00236-5journal_volume
24pub_type
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