Rutacecarpine Inhibits Angiogenesis by Targeting the VEGFR2 and VEGFR2-Mediated Akt/mTOR/p70s6k Signaling Pathway

Molecules. 2018 Aug 15;23(8):2047. doi: 10.3390/molecules23082047.


This study aimed to investigate the effect of Ru (Rut) on angiogenesis, and the underlying regulation mechanism of signal transduction. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, adhesion inhibition experiment, migration inhibition experiment, and chick embryo chorioallantoic membrane (CAM) assays were performed on models of angiogenesis. The potential targets of rutaecarpine (Ru) were reverse screened with Discovery Studio 2017. The interaction between the compound and target were detected by surface plasmon resonance (SPR), enzyme-activity experiment, and Western blot assay. The obtained results confirmed that Ru exhibited modest inhibitory activity against human umbilical vein endothelial cells (HUVECs) (IC50 =16.54 ± 2.4 μM) and remarkable inhibitive effect against the migration and adhesion of HUVECs, as well as significant anti-angiogenesis activities in the CAM assay. The possible targets of vascular endothelial growth factor receptor 2 (VEGFR2) were identified by computer-aided simulation. Results showed a good binding relationship between the ligand and target through molecular docking, and this relationship was confirmed by SPR analysis. Furthermore, enzyme-activity experiment and western blot assay showed that Ru remarkably inhibited the activity of VEGFR2 and blocked the VEGFR2-mediated Akt/ (mTOR)/p70s6k signaling pathway in vitro. Ru can be a potential drug candidate for cancer prevention and cancer therapy.

Keywords: Ru; VEGFR2; angiogenesis; reverse screen.

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Chick Embryo
  • Chorioallantoic Membrane / blood supply
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / physiology
  • Humans
  • Indole Alkaloids / pharmacology*
  • Molecular Docking Simulation / methods
  • Neovascularization, Physiologic / drug effects*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Quinazolines / pharmacology*
  • Rats
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism*
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*


  • Angiogenesis Inhibitors
  • Indole Alkaloids
  • Quinazolines
  • rutecarpine
  • Vascular Endothelial Growth Factor Receptor-2
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • TOR Serine-Threonine Kinases