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Gentisic acid, a compound associated with plant defense and a metabolite of aspirin, heads a new class of in vivo fibroblast growth factor inhibitors

AutorFernández, Israel S. ; López-Navajas, Pilar; Canales, Ángeles ; González-Corrochano, Rocío; Lozano, R.M. ; Jiménez-Barbero, Jesús ; Romero, Antonio ; Giménez-Gallego, Guillermo
Palabras claveCell/Migration
Diseases/Cancer/Therapy
Extracellular matrix/Heparan sulfate
Growth factors
Tumor/Therapy
Anti-angiogenesis
Heparin
Fecha de publicación9-abr-2010
EditorAmerican Society for Biochemistry and Molecular Biology
CitaciónJ Biol Chem. 285(15):11714-29 (2010)
ResumenFibroblast growth factors are key proteins in many intercellular signaling networks. They normally remain attached to the extracellular matrix, which confers on them a considerable stability. The unrestrained accumulation of fibroblast growth factors in the extracellular milieu, either due to uncontrolled synthesis or enzymatic release, contributes to the pathology of many diseases. Consequently, the neutralization of improperly mobilized fibroblast growth factors is of clear therapeutic interest. In pursuing described rules to identify potential inhibitors of these proteins, gentisic acid, a plant pest-controlling compound, an aspirin and vegetarian diet common catabolite, and a component of many traditional liquors and herbal remedies, was singled out as a powerful inhibitor of fibroblast growth factors. Gentisic acid was used as a lead to identify additional compounds with better inhibitory characteristics generating a new chemical class of fibroblast growth factor inhibitors that includes the agent responsible for alkaptonuria. Through low and high resolution approaches, using representative members of the fibroblast growth factor family and their cell receptors, it was shown that this class of inhibitors may employ two different mechanisms to interfere with the assembly of the signaling complexes that trigger fibroblast growth factor-driven mitogenesis. In addition, we obtained evidence from in vivo disease models that this group of inhibitors may be of interest to treat cancer and angiogenesis-dependent diseases.
Descripción21 p.-9 fig.-1 tab.-4 fig. supl. Fernández, Israel S. et al.
Versión del editorhttp://dx.doi.org/10.1074/jbc.M109.064618
URIhttp://hdl.handle.net/10261/155569
DOI10.1074/jbc.M109.064618
ISSN0021-9258
E-ISSN1083-351X
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