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

Abstract

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.

Antiangiogenic Effect of Flavonoids and Chalcones: An Update

“…Furthermore, several other flavonoids, such as galangin, myricetin, chrysin, hispidulin, nobiletin, delphinidin, barbigerone, eupatorin or wogonin, were found to inhibit the VEGF signaling pathway either due to a direct effect on VEGF/VEGFR2 or via modulation of VEGFR2-mediated downstream signaling [ 54 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 ].…”

Modulation of Adhesion Process, E-Selectin and VEGF Production by Anthocyanins and Their Metabolites in an In Vitro Model of Atherosclerosis

“…To support the hypothesis of the involvement of angiogenesis in atherosclerosis, Qiu et al showed that arterial regions with higher shear stress also exhibit an elevated number of intraplaque microvessels, characterized by abnormal endothelial cells, in particular with intracytoplasmatic vacuoles and leukocyte infiltration that could lead to rupture-prone plaque formation [39]. In cancer research, multiple in vitro studies demonstrated the anti-angiogenic effect of anthocyanins, in particular concerning delphinidin, as a potential chemopreventive agent [40][41][42]. We found that Peo-3-glc, Pet-3-glc and their metabolites (VA and MetGA) reduced the levels of VEGF, corroborating the hypothesis of a protective mechanism of action through which these compounds inhibit angiogenesis within the atheroma, therefore reducing atherosclerotic disease progression.…”

Anthocyanins, Vibrant Color Pigments, and Their Role in Skin Cancer Prevention

“…Moreover, the glycosylated B-ring in the structure of anthocyanins are highly effective regarding their antioxidant activity, where ortho-hydroxylation and methoxylation significantly increase the antioxidant activity [ 292 ]. Several in vitro studies have reported the antioxidant effect of anthocyanins when conducted on the colon [ 293 , 294 ], endothelial [ 295 ], liver [ 296 ], breast [ 226 , 239 ], leukemic [ 123 ] and keratinocytes [ 297 ], cervical [ 280 ] and melanoma [ 124 ] cell lines. In these studies, anthocyanins have shown to exhibit multiple anticarcinogenic effects from scavenging reactive oxygen species to reducing cell proliferation, from stimulating the expression of Phase II detoxification enzymes to inhibiting mutagenesis by environmental toxins and carcinogenesis, among others.…”