Delphinidin, a dietary anthocyanidin, inhibits platelet-derived growth factor ligand/receptor (PDGF/PDGFR) signaling

Abstract

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-beta [platelet-derived growth factor receptor-beta (PDGFR-beta)] in SMC and that this inhibition may contribute to its antitumor effect. The inhibitory effect of delphinidin on PDGFR-beta 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.

Baicalin inhibits PDGF-BB-stimulated vascular smooth muscle cell proliferation through suppressing PDGFRβ-ERK signaling and increase in p27 accumulation and prevents injury-induced neointimal hyperplasia

“…Baicalin belongs to a class of polyphenols. Previous studies have shown that polyphenols inhibit PDGFRβ autophosphorylation [19][20][21][22]. Although the mechanisms underlying the inhibitory effect of these polyphenols remain to be established, previous studies suggested that some of these molecules may inhibit the activation of receptor tyrosine kinase by competing with adenosine triphosphate for binding to the kinase domain of the receptor, resulting in impaired activation of key signaling intermediates [23,24].…”

Berry anthocyanin intake and cardiovascular health

“…These preliminary RCT findings are supported by animal and in vitro data. Anthocyanins inhibit atherosclerosis development, alter cell signalling pathways involved in vascular inflammation, and reduce infarct size following coronary occlusion and perfusion (Lamy et al 2008;Toufektsian et al 2008). Mechanistic studies also suggest an impact on whole body insulin action (DeFuria et al 2009;Inaguma, Han, and Isoda 2011;Stull et al 2010).…”

The Dietary Flavones Apigenin and Luteolin Impair Smooth Muscle Cell Migration and VEGF Expression through Inhibition of PDGFR-β Phosphorylation

“…Confluent pulmonary aortic smooth muscle cells were incubated for 18 h in 0.5% fetal bovine serum containing either vehicle (DMSO) or flavonoids and stimulated with 50 ng/mL PDGF-BB for 5 min. Cells were washed and solubilized on ice in lysis buffer [150 mmol/L NaCl, 10 mmol/L Tris-HCl (pH 7.4), 1 mmol/L EDTA, 1 mmol/L EGTA, 1 mmol/L NaF, 1 mmol/L Na 3 VO 4 , 0.5% (v/v) NP40, and 1% (v/v) Triton X-100], and the resulting lysates were processed for immunoprecipitation studies as previously described (26). Briefly, lysates (200 μg protein) from each sample were incubated in lysis buffer overnight at 4°C in the presence of 1 μg/mL of anti-PDGFR-β antibodies, and immune complexes were collected by incubating the mixture with 25 μL (50% suspension) of Protein A-Sepharose beads for 2 h. Bound proteins were solubilized in 2-fold concentrated Laemmli sample buffer [125 mmol/L Tris-HCl (pH 6.8), 20% glycerol, 4% SDS, 10% β-mercaptoethanol, and 0.00125% bromophenol blue], boiled for 4 min, and resolved by SDS-PAGE (7.5% gel).…”

“…The Matrigel plug assay was done essentially as described previously (26,27). Briefly, female nude mice (Crl:CD-1-Foxn1 nu ; 20-25 g, 6 wk of age; Charles River Laboratories) were treated by injection s. c. into the ventral midline region of the right flank with 0.5 mL of phenol red-free Matrigel (BD Bioscience) containing apigenin (25 μmol/L) or luteolin (50 μmol/L), FGF-2 (250 ng/mL), VEGF (200 ng/mL), and heparin (0.0025 units/mL).…”