Carcinogenesis Advance Access originally published online on March 13, 2008
Carcinogenesis 2008 29(5):1033-1041; doi:10.1093/carcin/bgn070
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Delphinidin, a dietary anthocyanidin, inhibits platelet-derived growth factor ligand/receptor (PDGF/PDGFR) signaling
1 Laboratoire de Médecine Moléculaire, Hôpital Ste-Justine-Université du Québec à Montréal
2 Service d'hématologie-oncologie, Centre de Cancérologie Charles-Bruneau, Hôpital Ste-Justine, 3175 Côte-Ste-Catherine, Montréal, Québec H3T 1C5, Canada
* To whom correspondence should be addressed. Tel: +514 345 4931 2366; Fax: +514 345 2359; Email: molmed{at}recherche-ste-justine.qc.ca
Most cancers are dependent on the growth of tumor blood vessels and inhibition of tumor angiogenesis may thus provide an efficient strategy to retard or block tumor growth. Recently, tumor vascular targeting has expanded to include not only endothelial cells (ECs) but also smooth muscle cells (SMCs), which contribute to a mature and functional vasculature. We have reported previously that delphinidin, a major biologically active constituent of berries, inhibits the vascular endothelial growth factor-induced phosphorylation of vascular endothelial growth factor receptor-2 and blocks angiogenesis in vitro and in vivo. In the present study, we show that delphinidin also inhibits activation of the platelet-derived growth factor (PDGF)-BB receptor-β [platelet-derived growth factor receptor-β (PDGFR-β)] in SMC and that this inhibition may contribute to its antitumor effect. The inhibitory effect of delphinidin on PDGFR-β was very rapid and led to the inhibition of PDGF-BB-induced activation of extracellular signal-regulated kinase (ERK)-1/2 signaling and of the chemotactic motility of SMC, as well as the differentiation and stabilization of EC and SMC into capillary-like tubular structures in a three-dimensional coculture system. Using an anthocyan-rich extract of berries, we show that berry extracts were able to suppress the synergistic induction of vessel formation by basic fibroblast growth factor-2 and PDGF-BB in the mouse Matrigel plug assay. Oral administration of the berry extract also significantly retarded tumor growth in a lung carcinoma xenograft model. Taken together, these results provide new insight into the molecular mechanisms underlying the antiangiogenic activity of delphinidin that will be helpful for the development of dietary-based chemopreventive strategies.
Abbreviations: EC, endothelial cell; ERK, extracellular signal-regulated kinase; FGF-2, fibroblast growth factor-2; HUVEC, human umbilical vein endothelial cell; PASMC, pulmonary aortic smooth muscle cell; PBS, phosphate-buffered saline; PDGF, platelet-derived growth factor; PDGFR-β, platelet-derived growth factor receptor-β; s.c., subcutaneous; SMC, smooth muscle cell; VEGF, vascular endothelial growth factor; VEGFR-2, vascular endothelial growth factor receptor-2
Received November 5, 2007; revised February 28, 2008; accepted March 7, 2008.
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