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Carcinogenesis Advance Access published online on January 20, 2005
Carcinogenesis, doi:10.1093/carcin/bgi024
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Oxford University Press
Received October 12, 2004
Revised December 10, 2004
Accepted January 8, 2005

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

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

Lyne Labrecque 1, Sylvie Lamy 1, Amélie Chapus 1, Samira Mihoubi 1, Yves Durocher 2, Brian Cass 2, Michel W. Bojanowski 3, Denis Gingras 1, and Richard Béliveau 1*

1 Laboratoire de Médecine Moléculaire, Hôpital Ste-Justine-Université du Québec à Montréal, Centre de Cancérologie Charles-Bruneau, 3175 Chemin Côte-Ste-Catherine, Montréal, Québec, Canada, H3T1C5
2 Animal Cell Technology Group, Biotechnology Research Institute, National Research Council Canada, 6100 Royalmount Avenue, Montréal, Québec, Canada, H4P2R2
3 Département de Neurochirugie, Hôpital Notre-Dame, 1560 rue Sherbrooke Est Montréal, Québec, Canada H2L4M1

* To whom correspondence should be addressed.
Richard Béliveau, E-mail: molmed{at}justine.umontreal.ca


  Abstract

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, a natural polyphenol found in fruits and nuts, inhibits VEGF-induced phosphorylation of VEGFR-2 in EC as well as PDGF-induced phosphorylation of PDGFR in smooth muscle cells, leading to the inhibition of downstream signaling triggered by these receptors. Ellagic acid also specifically inhibited VEGF-induced migration of endothelial cells as well as their differentiation into capillary-like tubular structures, and abolished PDGF-dependent smooth muscle cell migration. Interestingly, ellagic acid 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 ellagic acid 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.

* Supported by a grant from the Cancer Research Society to R.B.


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