Novel angiogenesis inhibitory activity in cinnamon extract blocks VEGFR2 kinase and downstream signaling.
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.
Lu
Jianming
J
Department of Molecular Medicine, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
Zhang
Keqiang
K
Nam
Sangkil
S
Anderson
Richard A
RA
Jove
Richard
R
Wen
Wei
W
D020533:Angiogenesis Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D044946:Biflavonoids / Q000302:isolation & purification / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology; D002392:Catechin / Q000302:isolation & purification / Q000494:pharmacology; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000201:enzymology / Q000637:transplantation; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D002642:Chick Embryo; D002935:Cinnamomum zeylanicum / Q000737:chemistry*; D003094:Collagen; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D005260:Female; D006801:Humans; D007797:Laminin; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009024:Morphogenesis / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology*; D044945:Proanthocyanidins / Q000302:isolation & purification / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011509:Proteoglycans; D015398:Signal Transduction / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D044946:Biflavonoids; D004338:Drug Combinations; D007797:Laminin; D010936:Plant Extracts; D044945:Proanthocyanidins; D011509:Proteoglycans; C059485:matrigel; C017674:procyanidin; D002392:Catechin; D003094:Collagen; D040301:Vascular Endothelial Growth Factor Receptor-2