Novel angiogenesis inhibitory activity in cinnamon extract blocks VEGFR2 kinase and downstream signaling
Novel angiogenesis inhibitory activity in cinnamon extract blocks VEGFR2 kinase and downstream signaling
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DOI：
10.1093/carcin/bgp292
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发表时间：
2010-03-01
期刊：
影响因子：
4.7
通讯作者：
Wen, Wei
中科院分区：
文献类型：
--
作者：
Lu, Jianming;Zhang, Keqiang;Wen, Wei
血管内皮生长因子（vascular endothelial growth factor，VEGF）作为诱导血管生成的关键因子，已成为抗血管生成治疗的重要靶点。然而，与大多数抗VEGF药物相关的副作用限制了它们的长期使用。从饮食中鉴定天然存在的VEGF抑制剂是一种潜在的替代方法，具有已知安全性的优点。为了分离VEGF的天然抑制剂，我们建立了体外酪氨酸激酶测定来筛选抑制VEGFR 2激酶活性的基于饮食的药剂。我们发现，肉桂（肉桂提取物，CE），最古老和最流行的香料之一，是一种有效的VEGFR 2激酶活性抑制剂，直接抑制纯化的VEGFR 2的激酶活性，以及丝裂原活化蛋白激酶和Stat 3介导的信号通路在内皮细胞。结果，CE抑制VEGF诱导的内皮细胞增殖、迁移和管形成，抑制离体主动脉环的芽形成和体内肿瘤诱导的血管形成。用聚乙烯吡咯烷酮耗尽CE中的多酚，则其抗血管生成活性消失。而肉桂醛，一个组件负责CE的香气，对VEGFR 2激酶活性的影响不大，高效液相色谱纯化的CE，矢车菊苷配质A型三聚体（分子量，864）和四聚体（分子量，1152）被发现抑制纯化的VEGFR 2和VEGFR 2信号的激酶活性，暗示矢车菊苷配质低聚物作为活性成分在CE中，抑制血管生成。我们的数据揭示了肉桂的一种新活性，并确定了一种天然的VEGF抑制剂，可能有助于癌症的预防和/或治疗。
As a critical factor in the induction of angiogenesis, vascular endothelial growth factor (VEGF) has become an attractive target for anti-angiogenesis treatment. However, the side effects associated with most anti-VEGF agents limit their chronic use. Identification of naturally occurring VEGF inhibitors derived from diet is a potential alternative approach, with the advantage of known safety. To isolate natural inhibitors of VEGF, we established an in vitro tyrosine kinase assay to screen for diet-based agents that suppress VEGFR2 kinase activity. We found that a water-based extract from cinnamon (cinnamon extract, CE), one of the oldest and most popular spices, was a potent inhibitor of VEGFR2 kinase activity, directly inhibiting kinase activity of purified VEGFR2 as well as mitogen-activated protein kinase- and Stat3-mediated signaling pathway in endothelial cells. As a result, CE inhibited VEGF-induced endothelial cell proliferation, migration and tube formation in vitro, sprout formation from aortic ring ex vivo and tumor-induced blood vessel formation in vivo. Depletion of polyphenol from CE with polyvinylpyrrolidone abolished its anti-angiogenesis activity. While cinnamaldehyde, a component responsible for CE aroma, had little effect on VEGFR2 kinase activity, high-performance liquid chromatography-purified components of CE, procyanidin type A trimer (molecular weight, 864) and a tetramer (molecular weight, 1152) were found to inhibit kinase activity of purified VEGFR2 and VEGFR2 signaling, implicating procyanidin oligomers as active components in CE that inhibit angiogenesis. Our data revealed a novel activity in cinnamon and identified a natural VEGF inhibitor that could potentially be useful in cancer prevention and/or treatment.