title: 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.
authors.affiliation: Laboratoire de Biophotonique et de Pharmacologie, CNRS UMR 7213, Université de Strasbourg, Illkirch, France.
authors.forename: Thérèse
authors.initials: T
authors.lastname: Keravis
authors.affiliation: Laboratoire de Biophotonique et de Pharmacologie, CNRS UMR 7213, Université de Strasbourg, Illkirch, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Favot
authors.affiliation: Laboratoire de Biophotonique et de Pharmacologie, CNRS UMR 7213, Université de Strasbourg, Illkirch, France.
authors.forename: Abdurrazag A
authors.initials: AA
authors.lastname: Abusnina
authors.affiliation: Laboratoire de Biophotonique et de Pharmacologie, CNRS UMR 7213, Université de Strasbourg, Illkirch, France.
authors.forename: Anita
authors.initials: A
authors.lastname: Anton
authors.affiliation: Laboratoire de Biophotonique et de Pharmacologie, CNRS UMR 7213, Université de Strasbourg, Illkirch, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Justiniano
authors.affiliation: LUNAM, INSERM, U1063, Université d'Angers, Angers, France.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Soleti
authors.affiliation: LUNAM, INSERM, U1063, Université d'Angers, Angers, France.
authors.forename: Eid
authors.initials: E
authors.lastname: Alabed Alibrahim
authors.affiliation: LUNAM, INSERM, U1063, Université d'Angers, Angers, France.|Centre Hospitalo-Universitaire, Angers, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Simard
authors.affiliation: LUNAM, INSERM, U1063, Université d'Angers, Angers, France.|Centre Hospitalo-Universitaire, Angers, France.
authors.forename: Ramaroson
authors.initials: R
authors.lastname: Andriantsitohaina
authors.affiliation: Laboratoire de Biophotonique et de Pharmacologie, CNRS UMR 7213, Université de Strasbourg, Illkirch, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Lugnier
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000872:Anthocyanins / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000872:Anthocyanins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C017185:delphinidin