Blockade of vascular endothelial growth factor receptors by tivozanib has potential anti-tumour effects on human glioblastoma cells

Sci Rep. 2017 Mar 13;7:44075. doi: 10.1038/srep44075.

Abstract

Glioblastoma (GBM) remains one of the most fatal human malignancies due to its high angiogenic and infiltrative capacities. Even with optimal therapy including surgery, radiotherapy and temozolomide, it is essentially incurable. GBM is among the most neovascularised neoplasms and its malignant progression associates with striking neovascularisation, evidenced by vasoproliferation and endothelial cell hyperplasia. Targeting the pro-angiogenic pathways is therefore a promising anti-glioma strategy. Here we show that tivozanib, a pan-inhibitor of vascular endothelial growth factor (VEGF) receptors, inhibited proliferation of GBM cells through a G2/M cell cycle arrest via inhibition of polo-like kinase 1 (PLK1) signalling pathway and down-modulation of Aurora kinases A and B, cyclin B1 and CDC25C. Moreover, tivozanib decreased adhesive potential of these cells through reduction of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Tivozanib diminished GBM cell invasion through impairing the proteolytic cascade of cathepsin B/urokinase-type plasminogen activator (uPA)/matrix metalloproteinase-2 (MMP-2). Combination of tivozanib with EGFR small molecule inhibitor gefitinib synergistically increased sensitivity to gefitinib. Altogether, these findings suggest that VEGFR blockade by tivozanib has potential anti-glioma effects in vitro. Further in vivo studies are warranted to explore the anti-tumour activity of tivozanib in combinatorial approaches in GBM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anoikis
  • Antineoplastic Agents / therapeutic use*
  • Brain Neoplasms / complications
  • Brain Neoplasms / drug therapy*
  • Cell Adhesion
  • Cell Cycle Checkpoints
  • Cell Line, Tumor
  • Cell Proliferation
  • Gefitinib
  • Glioblastoma / complications
  • Glioblastoma / drug therapy*
  • Humans
  • Neovascularization, Pathologic / complications
  • Neovascularization, Pathologic / drug therapy
  • Phenylurea Compounds / therapeutic use*
  • Quinazolines / therapeutic use
  • Quinolines / therapeutic use*
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*

Substances

  • Antineoplastic Agents
  • Phenylurea Compounds
  • Quinazolines
  • Quinolines
  • tivozanib
  • Receptors, Vascular Endothelial Growth Factor
  • Gefitinib