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Dadun > Depósito Académico > CIMA (Centro de Investigación Médica Aplicada) > Área de Oncología > Microambiente tumoral > DA - CIMA - Oncología - Microambiente tumoral - Artículos de revista >

Flavonoids inhibit hypoxia-induced vascular endothelial growth factor expression by a HIF-1 independent mechanism
Authors: Anso, E. (Elena)
Zuazo, A. (Alicia)
Irigoyen, M. (Marta)
Urdaci, M.C. (María C.)
Rouzaut, A. (Ana)
Martinez-Irujo, J.J. (Juan José)
Keywords: Flavonoids
Hypoxia
HIF
VEGF
Angiogenesis
STAT3
Issue Date: 2010
Publisher: Elsevier
Publisher version: http://www.sciencedirect.com/science/article/pii/S0006295210000985
ISSN: 1873-2968
Citation: Anso E, Zuazo A, Irigoyen M, Urdaci MC, Rouzaut A, Martinez-Irujo JJ. Flavonoids inhibit hypoxia-induced vascular endothelial growth factor expression by a HIF-1 independent mechanism. Biochem Pharmacol 2010 Jun 1;79(11):1600-1609.
Abstract
Flavonoids are a group of polyphenolic dietary compounds that have been proposed to possess chemopreventive properties against lung cancer. In this work we analyzed the effect of a group of 20 structurally related flavonoids, including flavones, flavonols and isoflavones, on the production of vascular endothelial growth factor (VEGF) induced by hypoxia in NCI-H157 cells. VEGF is the main regulator of physiological and pathological angiogenesis and is highly stimulated by hypoxia-inducible factor 1 (HIF-1). We found that apigenin, luteolin, fisetin and quercetin inhibited hypoxia-induced VEGF expression in the low micromolar range. Structure-activity relationships demonstrated that flavone derivatives were the most active compounds and that hydroxylation of the A ring at the positions 5 and 7 and of the B ring at the 4' position were important for this activity. Interestingly, only a group of VEGF inhibitors, including apigenin, flavone and 4',7-dihydroxiflavone, reduced the expression of HIF-1alpha under these conditions, whereas others, such as fisetin, luteolin, galangin or quercetin, induced HIF-1alpha expression while reducing those of VEGF. When cells were exposed to hypoxia in the presence of these flavonoids, HIF-1alpha translocated to the nucleus and interacted with p300/CBP, but this complex was transcriptionally inactive. Taken together these findings indicate that flavonoids impair VEGF transcription by an alternative mechanism that did not depend on nuclear HIF levels. We also found that flavonoids suppressed hypoxia-induced STAT3 tyrosine phosphorylation and that this activity correlated with their potency as VEGF inhibitors, suggesting that inhibition of STAT3 function may play a role in this process.
Permanent link: http://hdl.handle.net/10171/20254
Appears in Collections:DA - Farmacia - Orgánica - Artículos de revista
DA - Ciencias - Bioquímica y Biología molecular - Artículos de Revista
DA - CIMA - Oncología - Microambiente tumoral - Artículos de revista

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