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

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 (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.

Anthocyanidins inhibit migration of glioblastoma cells: Structure‐activity relationship and involvement of the plasminolytic system

“…Anti-mouse and anti-rabbit IgG horseradish peroxidase (HRP)-linked secondary antibodies were purchased from Jackson ImmunoResearch Laboratories (West Grove, PA) and enhanced chemiluminescence (ECL) reagents were from PerkinElmer Life Sciences (Boston, MA). Human recombinant vascular endothelial growth factor (VEGF; isoform 165) was produced and purified as described [Labrecque et al, 2005]. Epidermal growth factor (EGF) was purchased from BD Biosciences Discovery Labware (Bedford, MA).…”

Ellagic acid induces apoptosis through inhibition of nuclear factor kB in pancreatic cancer cells

“…Aliquots of mitochondrial suspension were collected, centrifuged at 13 500 g for 10 min at 4℃, and cytochrome C levels in the mitochondria (pellet) and the medium (supernatant) were measured by Western blot as previously described [13] . Preparation of nuclear extracts and electromobility shift assay (EMSA) Preparation of nuclear extracts and EMSA have been described in detail [17][18][19] . Briefly, pancreatic cancer cells were lysed on ice in a hypotonic buffer A [17] supplemented with 1 mmol/L PMSF, 1 mmol/L DTT, and protease inhibitor cocktail containing 5 μg/mL each of pepstatin, leupeptin, chymostatin, antipain, and aprotinin.…”

Treatment with Imatinib in NSCLC is associated with decrease of phosphorylated PDGFR-β and VEGF expression, decrease in interstitial fluid pressure and improvement of oxygenation

“…PDGFR-b is overexpressed in 50 -80% of patients with NSCLC (Kawai et al, 1997). When phosphorylated, PDGFR-b contributes to increased IFP by enhanced stimulation of stromal growth, which disrupts interstitial homeostasis (Heuchel et al, 1999;Ostman, 2004) and by participation in tumour angiogenesis (Pietras et al, 2001;Labrecque et al, 2005). Although VEGF is the predominate angiogenic factor that promotes endothelial cell (EC) proliferation, migration, vessel sprouting, vessel remodelling and vascular permeability (Dvorak et al, 1995), p-PDGFR-b is required for pericyte and smooth muscle cell recruitment and for the subsequent completion of the angiogenic process (Nykanen et al, 2005).…”