Impaired Angiogenesis and Tumor Development by Inhibition of the Mitotic Kinesin Eg5

Oncotarget. 2013 Dec;4(12):2302-16. doi: 10.18632/oncotarget.1490.

Abstract

Kinesin motor proteins exert essential cellular functions in all eukaryotes. They control mitosis, migration and intracellular transport through interaction with microtubules. Small molecule inhibitors of the mitotic kinesin KiF11/Eg5 are a promising new class of anti-neoplastic agents currently evaluated in clinical cancer trials for solid tumors and hematological malignancies. Here we report induction of Eg5 and four other mitotic kinesins including KIF20A/Mklp2 upon stimulation of in vivo angiogenesis with vascular endothelial growth factor-A (VEGF-A). Expression analyses indicate up-regulation of several kinesin-encoding genes predominantly in lymphoblasts and endothelial cells. Chemical blockade of Eg5 inhibits endothelial cell proliferation and migration in vitro. Mitosis-independent vascular outgrowth in aortic ring cultures is strongly impaired after Eg5 or Mklp2 protein inhibition. In vivo, interfering with KIF11/Eg5 function causes developmental and vascular defects in zebrafish and chick embryos and potent inhibition of tumor angiogenesis in experimental tumor models. Besides blocking tumor cell proliferation, impairing endothelial function is a novel mechanism of action of kinesin inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Growth Processes / drug effects
  • Cell Line, Tumor
  • Chick Embryo
  • Chorioallantoic Membrane / blood supply
  • Chorioallantoic Membrane / drug effects
  • Gene Expression / drug effects
  • Glioma / blood supply*
  • Glioma / drug therapy
  • Glioma / enzymology
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Kinesin / antagonists & inhibitors*
  • Kinesin / genetics
  • Kinesin / metabolism
  • Mice
  • Mitosis / drug effects
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / enzymology
  • Quinazolines / pharmacology
  • Recombinant Proteins / pharmacology
  • Thiones / pharmacology
  • Vascular Endothelial Growth Factor A / pharmacology
  • Zebrafish

Substances

  • KIF11 protein, human
  • Quinazolines
  • Recombinant Proteins
  • Thiones
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • dimethylenastron
  • Kif11 protein, mouse
  • Kinesin