Flavonoids inhibit hypoxia-induced vascular endothelial growth factor expression by a HIF-1 independent mechanism
Flavonoids inhibit hypoxia-induced vascular endothelial growth factor expression by a HIF-1 independent mechanism
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DOI：
10.1016/j.bcp.2010.02.004
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发表时间：
2010-06-01
影响因子：
5.8
通讯作者：
Martinez-Irujo, Juan J.
中科院分区：
文献类型：
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作者：
Anso, Elena;Zuazo, Alicia;Martinez-Irujo, Juan J.
黄酮类化合物是一组多酚类膳食化合物，已被提出具有对肺癌的化学预防特性。在这项工作中，我们分析了一组20个结构相关的黄酮类化合物，包括黄酮，黄酮醇和黄酮类化合物，对血管内皮生长因子（VEGF）的生产缺氧诱导的NCI-H157细胞的影响。VEGF是生理性和病理性血管生成的主要调节因子，并且受到缺氧诱导因子1（HIF-1）的高度刺激。我们发现，芹菜素，毛地黄黄酮，非瑟酮和槲皮素抑制缺氧诱导的VEGF表达在低微摩尔范围内。结构-活性关系表明，黄酮衍生物是最具活性的化合物，并且在5和7位的A环和在4'位的B环的羟基化对这种活性是重要的。有趣的是，只有一组VEGF抑制剂，包括芹菜素、黄酮和4 '，7-二氢黄酮，在这些条件下降低HIF-1 α的表达，而其他抑制剂，如非瑟酮、毛地黄黄酮、高良姜素或槲皮素，诱导HIF-1 α的表达，同时降低VEGF的表达。当细胞暴露于这些黄酮类化合物存在下的缺氧时，HIF-1 α易位到细胞核并与p300/CBP相互作用，但这种复合物在转录上是无活性的。总之，这些研究结果表明，类黄酮损害VEGF转录的替代机制，不依赖于核HIF水平。我们还发现，类黄酮抑制缺氧诱导的STAT 3酪氨酸磷酸化，这种活性与其作为VEGF抑制剂的效力相关，这表明STAT 3功能的抑制可能在这一过程中发挥作用。(C)2010年爱思唯尔公司All rights reserved.
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-1 alpha under these conditions, whereas others, such as fisetin, luteolin, galangin or quercetin, induced HIF-1 alpha expression while reducing those of VEGF. When cells were exposed to hypoxia in the presence of these flavonoids, HIF-1 alpha 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. (C) 2010 Elsevier Inc. All rights reserved.