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Delphinidin, a dietary anthocyanidin, inhibits platelet-derived growth factor ligand/receptor (PDGF/PDGFR) signaling
Sylvie Lamy1, Edith Beaulieu, David Labbé
1Laboratoire de Médecine Moléculaire, Hôpital Ste-Justine-Université du Québec à Montréal, Canada.
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.
Insights
Delphinidin, a berry compound, inhibits tumor blood vessel growth by targeting smooth muscle cells and blocking platelet-derived growth factor receptor-beta signaling. Berry extracts also show antitumor effects, suggesting potential for dietary cancer prevention.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Tumor growth relies on angiogenesis, the formation of new blood vessels.
- Targeting tumor vasculature, including endothelial cells (ECs) and smooth muscle cells (SMCs), is a key cancer treatment strategy.
- Delphinidin, a berry constituent, previously showed anti-angiogenic properties by inhibiting vascular endothelial growth factor receptor-2.
Purpose of the Study:
- To investigate delphinidin's effect on platelet-derived growth factor (PDGF)-BB receptor-beta (PDGFR-beta) signaling in SMCs.
- To determine if PDGFR-beta inhibition contributes to delphinidin's antitumor activity.
- To evaluate the anti-angiogenic and antitumor potential of berry extracts.
Main Methods:
- Assessed delphinidin's inhibition of PDGFR-beta activation in SMCs.
- Examined PDGF-BB-induced signaling pathways, including extracellular signal-regulated kinase (ERK)-1/2.
- Utilized a 3D co-culture system to study EC and SMC differentiation into capillary-like structures.
- Employed a mouse Matrigel plug assay to assess berry extract's effect on vessel formation.
- Tested berry extract's efficacy in a lung carcinoma xenograft model.
Main Results:
- Delphinidin rapidly inhibited PDGFR-beta activation in SMCs.
- This inhibition blocked PDGF-BB-induced ERK-1/2 signaling and SMC chemotactic motility.
- Delphinidin suppressed the differentiation and stabilization of ECs and SMCs into capillary-like structures.
- Berry extracts suppressed synergistic vessel formation induced by FGF-2 and PDGF-BB.
- Oral administration of berry extract significantly retarded tumor growth in vivo.
Conclusions:
- Delphinidin's inhibition of PDGFR-beta signaling in SMCs is a novel mechanism contributing to its anti-angiogenic and antitumor effects.
- Berry extracts possess significant anti-angiogenic and tumor-retarding properties.
- These findings support the development of dietary-based chemopreventive strategies using berry constituents like delphinidin.
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