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Título: Melanoma Activation of 3-O-(3,4,5-Trimethoxybenzoyl)-(-)-Epicatechin to a Potent Irreversible Inhibitor of Dihydrofolate Reductase
Fecha de publicación: 9-abr-2009
Cita bibliográfica: Molecular Pharmaceutics. Volumen 6. nº3. Páginas 883-894
ISSN: 1543-8384
Materias relacionadas: CDU::5 - Ciencias puras y naturales::57 - Biología::577 - Bioquímica. Biología molecular. Biofísica
Palabras clave: Melanoma
Dihydrofolate reductase
Prodrug activation
Resumen: Human melanoma is a significant clinical problem because it is resistant to treatment by most chemotherapeutic agents, including antifolates. It is therefore a desirable goal to develop a second generation of low-toxicity antifolate drugs to overcome acquired resistance to the prevention and treatment of this skin pathology. In our efforts to improve the stability and bioavailability of green tea polyphenols for cancer therapy, we synthesized a trimethoxy derivative of epicatechin-3-gallate, which showed high anti proliferative and proapoptotic activity against melanoma. This derivative, 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin (TMECG), is a prodrug that is selectively activated by the specific melanocyte enzyme tyrosinase. Upon activation, TMECG generates a stable quinone methide product that strongly inhibits dihydrofolate reductase in an irreversible manner. The treatment of melanoma cells with TMECG also affected cellular folate transport and the gene expression of DHFR, which supported the antifolate nature of this compound. In addition, its pharmacological efficacy has been confirmed in a mouse melanoma model, in which tumor growth and metastasis were inhibited, significantly enhancing the mean survival of the treated groups. TMECG, therefore, shows a potential for clinical use in melanoma therapy.
Autor/es principal/es: Sánchez del Campo Ferrer, Luis
Tárraga Tomás, Alberto
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
Versión del editor: https://doi.org/10.1021/mp800259k
URI: http://hdl.handle.net/10201/136891
DOI: https://doi.org/10.1021/mp800259k
Tipo de documento: info:eu-repo/semantics/article
Número páginas / Extensión: 37
Derechos: info:eu-repo/semantics/openAccess
Descripción: This is an Accepted Manuscript version of the following article, accepted for publication in [Molecular Pharmaceutics]. [Sánchez-del-Campo L, Tárraga A, Montenegro MF, Cabezas-Herrera J, Rodríguez-López JN. Melanoma activation of 3-o-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin to a potent irreversible inhibitor of dihydrofolate reductase. Mol Pharm. 2009 May-Jun;6(3):883-94. doi: 10.1021/mp800259k]. It is deposited under the terms of the Creative Commons Attribution-Non Commercial License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
©2009. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ This document is the Accepted version of a Published Work that appeared in final form in Molecular Pharmaceutics. To access the final edited and published work see https://doi.org/10.1021/mp800259k
Aparece en las colecciones:Artículos: Bioquímica y Biología Molecular "A"

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