期刊
CANCER CELL
卷 24, 期 1, 页码 105-119出版社
CELL PRESS
DOI: 10.1016/j.ccr.2013.05.009
关键词
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资金
- Ministerio de Ciencia e Innovacion (MICINN) [SAF2009-12043-C02-01]
- Fundacion Seneca, Region de Murcia (FS-RM) [15230/PI/10]
- EU [ERA293514]
- FFIS
- MICINN
- FS-RM
- Fundacion de la Asociacion Espanola Contra el Cancer (FAECC)
- Ludwig Institute for Cancer Research
- Cancer Research UK [8466] Funding Source: researchfish
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-trimethoxybenzoyI)-(-)-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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