The vasculoprotective properties of
delphinidin are driven mainly by its action on endothelial cells. Moreover,
delphinidin displays anti-angiogenic properties in both in vitro and in vivo angiogenesis models and thereby might prevent the development of
tumors associated 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 endothelial 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
delphinidin was reversed either by the MEK1/2 MAP
kinase inhibitor,
U-0126, or the PI3K inhibitor,
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
melanoma cell in vivo by acting specifically on endothelial cell proliferation. The mechanism implies an association between inhibition of
VEGF-induced proliferation via VEGFR2 signalling, 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 promising compound to prevent pathologies associated with generation of vascular network in
tumorigenesis.