Grape seed proanthocyanidins inhibit angiogenesis via the downregulation of both vascular endothelial growth factor and angiopoietin signaling |
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Authors: | Shuangsheng Huang Ninggang Yang Yuanyuan Liu Lamei Hu Jin Zhao Jing Gao Yongquan Li Caili Li Xiaosu Zhang Tao Huang |
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Affiliation: | 1. Medical College of Northwest University for Nationalities, Lanzhou 730030, China;2. Department of Urology, Lanzhou First People''s Hospital, Lanzhou, 730030, China;3. Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China;4. Institute of Pharmacology, School of Basic Medical Science, Lanzhou University, Lanzhou 730000, China |
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Abstract: | Vascular endothelial growth factor (VEGF)/VEGF receptor 2 and angiopoietin 1/tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 signaling pathways regulate different, but complementary, aspects of blood vessel growth in tumors. Simultaneous inhibition of both pathways not only exhibits additive antiangiogenic effects but also overcomes the resistance to anti-VEGF therapy. Grape seed proanthocyanidins (GSPs) are widely consumed dietary supplements with antiangiogenic activity. However, the molecular mechanisms underlying their antiangiogenic action have not been fully understood. We hypothesized that GSPs modulate multiple signaling pathways to exhibit antiangiogenic effects. In the present study, we aimed to test this hypothesis by examining the effects of GSPs on human microvascular endothelial cell–1 and chick chorioallantoic membrane. Our results showed that GSPs inhibited the migration, matrix metalloproteinase–2 and –9 secretion, and tube formation of human microvascular endothelial cell–1 in vitro in a dose-dependent manner. In addition, chick chorioallantoic membrane angiogenesis assay showed that GSPs inhibited neovascularization in a dose-dependent manner. Furthermore, we demonstrated that GSPs inhibited the phosphorylation of VEGF receptor 2 and tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 as well as downstream signaling component extracellular signal–regulated kinase 1/2. In summary, these data suggest that GSPs inhibit both VEGF and angiopoietin 1 signaling to execute the antiangiogenic effects and indicate that GSPs could be developed as a pharmacologically safe chemopreventive agent against cancer. |
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Keywords: | Ang, angiopoietin CAM, chorioallantoic membrane ERK, extracellular signal&ndash regulated kinase FBS, fetal bovine serum GSPs, grape seed proanthocyanidins HMEC-1, human microvascular endothelial cell-1 MAPK, mitogen-activated protein kinase MMP, matrix metalloproteinase SRB, sulforhodamine B Tie2, tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 VEGF, vascular endothelial growth factor VEGFR2, vascular endothelial growth factor receptor 2 |
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