Delphinidin Inhibits Tumor Growth by Acting on VEGF Signalling in Endothelial Cells

Thérèse Keravis, Laure Favot, Abdurrazag A. Abusnina, Anita Anton, Hélène Justiniano, Raffaella Soleti, Eid Alabed Alibrahim, Gilles Simard, Ramaroson Andriantsitohaina & Claire Lugnier

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Mots clés: HUVEC, B16-F10 melanoma cell xenograft in mice, VEGFR2-mediated endothelial cell proliferation, CREB,Cyclic nucleotide phosphodiesterases

The vasculoprotective properties of delphinidin are driven mainly by its action on endothe- lial cells. Moreover, delphinidin displays anti-angiogenic properties in both in vitro and in vivo angiogenesis models and thereby might prevent the development of tumors associ- ated with excessive vascularization. This study was aimed to test the effect of delphinidin on melanoma-induced tumor growth with emphasis on its molecular mechanism on endo- thelial cells. Delphinidin treatment significantly decreased in vivo tumor growth induced by B16-F10 melanoma cell xenograft in mice. In vitro, delphinidin was not able to inhibit VEGFR2-mediated B16-F10 melanoma cell proliferation but it specifically reduced basal and VEGFR2-mediated endothelial cell proliferation. The anti-proliferative effect of delphi- nidin was reversed either by the MEK1/2 MAP kinase inhibitor, U-0126, or the PI3K inhibi- tor, LY-294002. VEGF-induced proliferation was reduced either by U-0126 or LY-294002. Under these conditions, delphinidin failed to decrease further endothelial cell proliferation. Delphinidin prevented VEGF-induced phosphorylation of ERK1/2 and p38 MAPK and decreased the expression of the transcription factors, CREB and ATF1. Finally, delphinidin was more potent in inhibiting in vitro cyclic nucleotide phosphodiesterases (PDEs), PDE1 and PDE2, compared to PDE3-PDE5. Altogether delphinidin reduced tumor growth of mel- anoma cell in vivo by acting specifically on endothelial cell proliferation. The mechanism implies an association between inhibition of VEGF-induced proliferation via VEGFR2 sig- nalling, MAPK, PI3K and at transcription level on CREB/ATF1 factors, and the inhibition of PDE2. In conjunction with our previous studies, we demonstrate that delphinidin is a prom- ising compound to prevent pathologies associated with generation of vascular network in tumorigenesis.

Keravis et al. (2015) PLoS ONE, 10: e0145291. DOI: 10.1371/journal.pone.0145291.

URL: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0145291