TKI-31 inhibits angiogenesis by combined suppression signaling pathway of VEGFR2 and PDGFRbeta

Cancer Biol Ther. 2006 Mar;5(3):323-30. doi: 10.4161/cbt.5.3.2543. Epub 2006 Mar 23.

Abstract

Tyrosine kinases have been strongly implicated as therapeutic targets that influence the angiogenic process in growing tumors. In this study, we revealed that TKI-31 is a potent broad spectrum tyrosine kinase inhibitor, which inhibits vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor beta (PDGFRbeta) and also inhibits kinases of other class, such as c-Kit and c-Src on molecular base, but showed no activity against vascular endothelial growth factor receptor 1 (VEGFR1) and epidermal growth factor receptor (EGFR). TKI-31 inhibits VEGF-induced phosphorylation of VEGFR2 in endothelial cells as well as PDGF(BB)-induced phosphorylation in fibroblast cells, and leading to the inhibition of down-stream signaling triggered by these receptors such as PI3K/Akt/mTOR, MAPK42/44(ERK) and paxillin. TKI-31 also inhibited VEGF-induced endothelial cells proliferation, migration and their differentiation into capillary-like tube formation. Its anti-angiogenic property was further confirmed by the inhibition of neovascularization on CAM, in vivo. These results collectively highlight the therapeutic potential of this compound for the treatment of solid tumors and other diseases where angiogenesis plays an important role.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / chemistry
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects*
  • Cell Survival / drug effects
  • Chick Embryo
  • Chorioallantoic Membrane / blood supply
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects*
  • Endothelial Cells / physiology
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Immunoblotting
  • Mice
  • NIH 3T3 Cells
  • Neovascularization, Physiologic / drug effects*
  • Phosphorylation
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology*
  • Receptor, Platelet-Derived Growth Factor beta / metabolism*
  • Recombinant Proteins
  • Signal Transduction
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*

Substances

  • Angiogenesis Inhibitors
  • Enzyme Inhibitors
  • Pyridines
  • Pyrimidinones
  • Recombinant Proteins
  • TKI-31
  • Protein-Tyrosine Kinases
  • Receptor, Platelet-Derived Growth Factor beta
  • Vascular Endothelial Growth Factor Receptor-2