Brucine, an indole alkaloid from Strychnos nux-vomica attenuates VEGF-induced angiogenesis via inhibiting VEGFR2 signaling pathway in vitro and in vivo

Cancer Lett. 2013 May 10;332(1):83-93. doi: 10.1016/j.canlet.2013.01.012. Epub 2013 Jan 21.

Abstract

In this study, we investigated the mechanism of brucine in tumor angiogenesis. We found that brucine inhibits VEGF-induced cell proliferation, chemotactic motility, and the formation of capillary-like structures in HUVECs in a dose-dependent manner. Brucine suppresses VEGF- induced p-VEGFR2 kinase activity and inhibits neovascularization in vivo. Brucine inhibits the downstream protein kinases of VEGFR2, including Src, FAK, ERK, AKT and mTOR. And further downregulates levels of VEGF, NO, IL-6, IL-8, TNF-α and IFN-γ in HUVECs. Taken together, our study suggests that brucine potently suppresses angiogenesis by targeting VEGFR2 activation and may be a viable drug candidate in anti-angiogenesis and anti-cancer therapies.

MeSH terms

  • Angiogenesis Inhibitors / isolation & purification
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Carcinoma, Ehrlich Tumor / blood supply
  • Carcinoma, Ehrlich Tumor / drug therapy
  • Carcinoma, Ehrlich Tumor / metabolism
  • Carcinoma, Ehrlich Tumor / pathology
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Chemotaxis / drug effects
  • Cytokines / metabolism
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression Regulation
  • Human Umbilical Vein Endothelial Cells / drug effects*
  • Human Umbilical Vein Endothelial Cells / enzymology
  • Humans
  • Male
  • Mice
  • Neovascularization, Physiologic / drug effects*
  • Nitric Oxide / metabolism
  • Phosphorylation
  • Plants, Medicinal
  • Protein Kinase Inhibitors / isolation & purification
  • Protein Kinase Inhibitors / pharmacology*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects*
  • Strychnine / analogs & derivatives*
  • Strychnine / isolation & purification
  • Strychnine / pharmacology
  • Strychnos nux-vomica* / chemistry
  • Time Factors
  • Tissue Culture Techniques
  • Tumor Burden / drug effects
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Angiogenesis Inhibitors
  • Cytokines
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • Vascular Endothelial Growth Factor A
  • Nitric Oxide
  • brucine
  • Vascular Endothelial Growth Factor Receptor-2
  • Strychnine