Didymin by suppressing NF-κB activation prevents VEGF-induced angiogenesis in vitro and in vivo

Vascul Pharmacol. 2019 Apr:115:18-25. doi: 10.1016/j.vph.2019.01.002. Epub 2019 Jan 8.

Abstract

Although didymin, a dietary flavonoid glycoside from citrus fruits, known to be a potent antioxidant with anti-cancer activities, its role in angiogenesis is not known. In this study, we examined the effect of didymin on VEGF-induced angiogenesis in vitro and in vivo models. Our results suggest that treatment of human umbilical vein endothelial cell (HUVECs) with didymin significantly prevented the VEGF-induced cell proliferation, migration, and invasion. Further, didymin significantly prevented the VEGF-induced endothelial tube formation in culture. Didymin also attenuated the VEGF-induced generation of ROS, activation of NF-κB and the expression of adhesion molecules such as VCAM-1, ICAM-1, and E-selectin in HUVECs. Further, didymin also prevented the VEGF-induced microvessel sprouting in ex vivo mouse aortic rings. Most importantly, didymin significantly prevented the invasion of endothelial cells and formation of blood capillary-like structures in Matrigel plug model of angiogenesis in mice. Thus, our results suggest a novel antiangiogenic efficacy of didymin in addition to its reported anti-cancer properties, which warrant further development of this agent for cancer therapy.

Keywords: Angiogenesis; Didymin; HUVEC; Neovascularization; VEGF.

MeSH terms

  • Angiogenesis Inducing Agents / pharmacology*
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Cell Adhesion Molecules / metabolism
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Flavonoids / pharmacology*
  • Glycosides / pharmacology*
  • Human Umbilical Vein Endothelial Cells / drug effects*
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Male
  • Mice, Inbred C57BL
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Neovascularization, Physiologic / drug effects*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Vascular Endothelial Growth Factor A / pharmacology*

Substances

  • Angiogenesis Inducing Agents
  • Angiogenesis Inhibitors
  • Cell Adhesion Molecules
  • Flavonoids
  • Glycosides
  • NF-kappa B
  • Reactive Oxygen Species
  • Vascular Endothelial Growth Factor A
  • didymin