Combined inhibition of PDGF and VEGF receptors by ellagic acid, a dietary-derived phenolic compound

• Published in: Carcinogenesis (New York) Vol. 26; no. 4; pp. 821 - 826
• Main Authors: Labrecque, Lyne, Lamy, Sylvie, Chapus, Amélie, Mihoubi, Samira, Durocher, Yves, Cass, Brian, Bojanowski, Michel W., Gingras, Denis, Béliveau, Richard
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.04.2005; Oxford Publishing Limited (England)
• Subjects: Animals; BAEC; Biological and medical sciences; bovine aortic endothelial cell; Carcinogenesis, carcinogens and anticarcinogens; Cattle; Cell Movement - drug effects; Cells, Cultured; Diet; EGF; EGFR; ellagic acid; Ellagic Acid - pharmacology; endothelial cell; Endothelium, Vascular - drug effects; epidermal growth factor; epidermal growth factor receptor; human umbilical vein endothelial cell; Humans; HUVEC; Medical sciences; Muscle, Smooth, Vascular - drug effects; Neoplasms - metabolism; Neoplasms - pathology; Neovascularization, Pathologic - prevention & control; PASMC; PDGF; PDGFR; Phosphorylation; platelet-derived growth factor; platelet-derived growth factor receptor; pulmonary aortic smooth muscle cell; Receptors, Platelet-Derived Growth Factor - antagonists & inhibitors; Receptors, Platelet-Derived Growth Factor - metabolism; S1P; sphingosine-1 phosphate; Tumors; vascular endothelial growth factor; vascular endothelial growth factor receptor-2; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - metabolism; vascular smooth muscle cells; VEGF; VEGFR-2; vSMC; Antineoplastic agent; Hemostatic; Antimutagen; Oral administration; Feeding; Vascular endothelium growth factor; Diet; Ellagic acid; Inhibitor; Phenoplasts; Inhibition; Platelet derived growth factor; Biological receptor
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgi024

The vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors play essential and complementary roles in angiogenesis and combined inhibition of these receptors has been shown to result in potent antitumor activity in vivo. In this study, we report that ellagic acid (EA), a natural polyphenol found in fruits and nuts, inhibits VEGF-induced phosphorylation of VEGFR-2 in endothelial cell (EC) as well as PDGF-induced phosphorylation of PDGFR in smooth muscle cells, leading to the inhibition of downstream signaling triggered by these receptors. EA also specifically inhibited VEGF-induced migration of ECs as well as their differentiation into capillary-like tubular structures and abolished PDGF-dependent smooth muscle cell migration. Interestingly, EA presents a greater selectivity for normal cells than for tumor cells since the migration of the U87 and HT1080 cell lines were much less affected by this molecule. The identification of EA as a naturally occurring dual inhibitor of VEGF and PDGF receptors suggests that this molecule possesses important antiangiogenic properties that may be helpful for the prevention and treatment of cancer.