Grape seed extract inhibits angiogenesis via suppression of the vascular endothelial growth factor receptor signaling pathway.
Blockade of angiogenesis is an important approach for cancer treatment and prevention. Vascular endothelial growth factor (VEGF) is one of the most critical factors that induce angiogenesis and has thus become an attractive target for antiangiogenesis treatment. However, most current anti-VEGF agents often cause some side effects when given chronically. Identification of naturally occurring VEGF inhibitors derived from diet would be one alternative approach with an advantage of known safety. Grape seed extract (GSE), a widely used dietary supplement, is known to have antitumor activity. In this study, we have explored the activity of GSE on VEGF receptor and angiogenesis. We found that GSE could directly inhibit the kinase activity of purified VEGF receptor 2, a novel activity of GSE that has not been characterized. GSE could also inhibit the VEGF receptor/mitogen-activated protein kinase-mediated signaling pathway in endothelial cells. As a result, GSE could inhibit VEGF-induced endothelial cell proliferation and migration as well as sprout formation from aorta ring. In vivo assay further showed that GSE could inhibit tumor growth and tumor angiogenesis of MDA-MB-231 breast cancer cells in mice. Consistent with the in vitro data, GSE treatment of tumor-bearing mice led to concomitant reduction of blood vessel density and phosphorylation of mitogen-activated protein kinase. Depletion of polyphenol with polyvinylpyrrolidone abolished the antiangiogenic activity of GSE, suggesting a water-soluble fraction of polyphenol in GSE is responsible for the antiangiogenic activity. Taken together, this study indicates that GSE is a well-tolerated and inexpensive natural VEGF inhibitor and could potentially be useful in cancer prevention or treatment.
Wen
Wei
W
Department of Molecular Medicine, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA. wwen@coh.org
Lu
Jianming
J
Zhang
Keqiang
K
Chen
Shiuan
S
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002645:Chickens; D042783:Endothelial Cells / Q000187:drug effects; D056604:Grape Seed Extract; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010936:Plant Extracts / Q000494:pharmacology*; D044945:Proanthocyanidins / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D056604:Grape Seed Extract; C511402:Grape Seed Proanthocyanidins; D010936:Plant Extracts; D044945:Proanthocyanidins; D040262:Receptors, Vascular Endothelial Growth Factor