Mechanism of Dihydrofolate Reductase Downregulation in Melanoma by 3-O-(3,4,5-Trimethoxybenzoyl)-(-)-Epicatechin

Sánchez del Campo Ferrer, Luis; Chazarra Parres, Soledad; Montenegro Arce, María Fernanda; Cabezas Herrera, Juan; Rodríguez López, José Neptuno

Publication:
Mechanism of Dihydrofolate Reductase Downregulation in Melanoma by 3-O-(3,4,5-Trimethoxybenzoyl)-(-)-Epicatechin

dc.contributor.author	Sánchez del Campo Ferrer, Luis
dc.contributor.author	Chazarra Parres, Soledad
dc.contributor.author	Montenegro Arce, María Fernanda
dc.contributor.author	Cabezas Herrera, Juan
dc.contributor.author	Rodríguez López, José Neptuno
dc.contributor.department	Bioquímica y Biología Molecular A	es
dc.date.accessioned	2024-01-04T09:24:40Z
dc.date.available	2024-01-04T09:24:40Z
dc.date.issued	2010-06-01
dc.description	© 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	es
dc.description.abstract	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	es
dc.format	application/pdf	es
dc.format.extent	32	es
dc.identifier.doi	https://doi.org/10.1002/jcb.22656
dc.identifier.eisbn	Journal of Cellular Biochemistry Volume 110, Issue 6 pp. 1399-1409	es
dc.identifier.issn	Print: 0730-2312
dc.identifier.issn	Electronic:1097-4644
dc.identifier.uri	http://hdl.handle.net/10201/137021
dc.language	eng	es
dc.publisher	WILEY	es
dc.relation	Ámbito del proyecto: Nacional o regional. Agencia financiadora: Ministerio de Ciencia e Innovación y Fundación Séneca, Región de Murcia Código o número del acuerdo de subvención: SAF2009-12043-C02-01, 08595/PI/08	es
dc.relation.isreplacedby	https://doi.org/10.1002/jcb.22656].	es
dc.rights	info:eu-repo/semantics/openAccess	es
dc.rights	Attribution-NonCommercial-NoDerivatives 4.0 Internacional	*
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/4.0/	*
dc.subject	Melanoma	es
dc.subject	Fólico,	es
dc.subject	Ácido	es
dc.subject	Gene expression	es
dc.subject	Dihydrofolate reductase	es
dc.subject	Hydrogen peroxide	es
dc.subject.other	CDU::5 - Ciencias puras y naturales::57 - Biología::577 - Bioquímica. Biología molecular. Biofísica	es
dc.title	Mechanism of Dihydrofolate Reductase Downregulation in Melanoma by 3-O-(3,4,5-Trimethoxybenzoyl)-(-)-Epicatechin	es
dc.type	info:eu-repo/semantics/article	es
dspace.entity.type	Publication	es