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Título: Mechanism of Dihydrofolate Reductase Downregulation in Melanoma by 3-O-(3,4,5-Trimethoxybenzoyl)-(-)-Epicatechin
Fecha de publicación: 1-jun-2010
Editorial: WILEY
Cita bibliográfica: Journal of Cellular Biochemistry Volume 110, Issue 6 pp. 1399-1409
ISSN: Print: 0730-2312
Materias relacionadas: CDU::5 - Ciencias puras y naturales::57 - Biología::577 - Bioquímica. Biología molecular. Biofísica
Palabras clave: Melanoma
Gene expression
Dihydrofolate reductase
Hydrogen peroxide
Resumen: In our search to improve the stability and cellular absorption of tea polyphenols, we synthesized 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin (TMECG), which showed high antiproliferative activity against melanoma. TMECG downregulates dihydrofolate reductase (DHFR) expression in melanoma cells and we detail the sequential mechanisms that result from this even. TMECG is specifically activated in melanoma cells to form a stable quinone methide (TMECG-QM). TMECG-QM has a dual action on these cells. First, it acts as a potent antifolate compound, disrupting folate metabolism and increasing intracellular oxidized folate coenzymes, such as dihydrofolate, which is a noncompetitive inhibitor of dihydropterine reductase, an enzyme essential for tetrahydrobiopterin (H4B) recycling. Such inhibition results in H4B deficiency, endothelial nitric oxide synthase (eNOS) uncoupling and superoxide production. Second, TMECG-QM acts as an efficient superoxide scavenger and promotes intra-cellular H2O2 accumulation. Here, we present evidence that TMECG markedly reduces melanoma H4B and NO bioavailability and that TMECG action is abolished by the eNOS inhibitor N-omega-nitro-L-arginine methyl ester or the H2O2 scavenger catalase, which strongly suggests H2O2-dependent DHFR downregulation. In addition, the data presented here indicate that the simultaneous targeting of important pathways for melanoma survival, such as the folate cycle, H4B recycling, and the eNOS reaction, could represent an attractive strategy for fighting this malignant skin pathology
Autor/es principal/es: Sánchez del Campo Ferrer, Luis
Chazarra Parres, Soledad
Montenegro Arce, María Fernanda
Cabezas Herrera, Juan
Rodríguez López, José Neptuno
Facultad/Departamentos/Servicios: Facultades, Departamentos, Servicios y Escuelas::Departamentos de la UMU::Bioquímica y Biología Molecular A
URI: http://hdl.handle.net/10201/137021
DOI: https://doi.org/10.1002/jcb.22656
Tipo de documento: info:eu-repo/semantics/article
Número páginas / Extensión: 32
Derechos: info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
Descripción: © 2010. The authors. This is the peer reviewed version of the following article: [Sánchez-del-Campo L, Chazarra S, Montenegro MF, Cabezas-Herrera J, Rodríguez-López JN. Mechanism of dihydrofolate reductase downregulation in melanoma by 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin. J Cell Biochem. 2010 Aug 15;110(6):1399-409, which has been published in final form at https://doi.org/10.1002/jcb.22656
Aparece en las colecciones:Artículos: Bioquímica y Biología Molecular "A"

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