Tumor cytotoxicity and endothelial Rac inhibition induced by TNP-470 in anaplastic thyroid cancer

Mol Cancer Ther. 2007 Apr;6(4):1329-37. doi: 10.1158/1535-7163.MCT-06-0554.

Abstract

Anaplastic thyroid carcinoma is an aggressive form of cancer with no treatment. Angiogenesis inhibitors, such as TNP-470, a synthetic derivative of fumagillin, have been shown to reduce tumor size and increase survival in heterotopic animal models of thyroid cancer. Our goals were to determine the effect of TNP-470 on anaplastic thyroid cancer using an orthotopic murine model, to identify the molecular pathways of TNP-470 actions on endothelial cells, and to determine the non-endothelial tumor effects of TNP-470. We injected human anaplastic thyroid carcinoma cells (DRO'90) into the thyroid glands of nude mice. Mice received TNP-470 (30 mg/kg) s.c. for 6 weeks. TNP-470 prolonged survival and reduced liver metastases. TNP-470 had direct cytotoxic effects on anaplastic thyroid carcinoma cells in vitro and in vivo. Paradoxically, TNP-470 increased vascular endothelial growth factor secretion from tumor cells in vitro and in vivo. However, there was no associated increase in tumor microvessel density. In endothelial cells, TNP-470 prevented vascular endothelial growth factor-induced endothelial permeability, intercellular gap formation, and ruffle formation by preventing Rac1 activation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Apoptosis / drug effects
  • Carcinoma / enzymology
  • Carcinoma / pathology*
  • Cell Line, Tumor
  • Cell Membrane Permeability / drug effects
  • Cell Proliferation / drug effects
  • Cell Surface Extensions / drug effects
  • Cyclohexanes / pharmacology*
  • Cyclohexanes / therapeutic use
  • Cytoskeleton / drug effects
  • Cytotoxicity, Immunologic / drug effects*
  • Disease Models, Animal
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Enzyme Activation / drug effects
  • Gap Junctions / drug effects
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis
  • O-(Chloroacetylcarbamoyl)fumagillol
  • Sesquiterpenes / pharmacology*
  • Sesquiterpenes / therapeutic use
  • Survival Analysis
  • Thyroid Neoplasms / drug therapy
  • Thyroid Neoplasms / enzymology
  • Thyroid Neoplasms / pathology*
  • Vascular Endothelial Growth Factor A / blood
  • rac GTP-Binding Proteins / antagonists & inhibitors*

Substances

  • Angiogenesis Inhibitors
  • Cyclohexanes
  • Sesquiterpenes
  • Vascular Endothelial Growth Factor A
  • rac GTP-Binding Proteins
  • O-(Chloroacetylcarbamoyl)fumagillol