Targeting the methionine cycle for melanoma therapy with 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin.
The higher expression of methionine cycle genes in melanoma cells than in normal melanocytes may be related with increased protein synthesis and transmethylation reactions and the subsequent need for high levels of methionine. 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin (TMECG), a trimethoxy derivative of epicatechin-3-gallate (ECG), effectively suppressed proliferation of melanoma cells in cultures by inducing apoptosis. TMECG modulates the expression of genes involved in methionine metabolism, cellular methylation and glutathione synthesis in melanoma cells. TMECG treatment of melanoma cells resulted in the downregulation of antiapoptotic Bcl-2, the upregulation of proapoptotic Bax and the activation of caspase-3; however, it did not induce the expression of the apoptosis protease-activating factor-1 (Apaf-1). Having elucidated the effects of TMECG on the melanoma methionine cycle, we designed therapeuthical strategies to increase its effectiveness. Combinations of TMECG with S-adenosylmethionine or compounds that modulate the intracellular concentration of adenosine strongly increase the antiproliferative effects of TMECG. The ability of TMECG to target multiple aspects related with melanoma survival, with a high degree of potency, points to its clinical value in melanoma therapy.
Sánchez-del-Campo
Luís
L
Department of Biochemistry and Molecular Biology A, School of Biology, University of Murcia, Murcia, Spain.
Rodríguez-López
José Neptuno
JN
D000241:Adenosine / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D017931:DNA Primers; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005978:Glutathione / Q000096:biosynthesis; D006801:Humans; D008545:Melanoma / Q000188:drug therapy*; D008715:Methionine / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
C529447:3-O-(3,4,5-trimethoxybenzoyl)epicatechin; D000970:Antineoplastic Agents; D017931:DNA Primers; D017382:Reactive Oxygen Species; D002392:Catechin; D008715:Methionine; D053148:Caspase 3; D005978:Glutathione; D000241:Adenosine