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

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.

• Authors: Dorit Nahari, Ronit Satchi-Fainaro, Ming Chen, Ian Mitchell, Laurie B Task, Zijuan Liu, Jason Kihneman, Allison B Carroll, Lance S Terada, Fiemu E Nwariaku
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 6 Issue 4 Pg. 1329-37 (Apr 2007) ISSN: 1535-7163 [Print] United States
• PMID: 17431111 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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