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

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

Research output: Contribution to journalArticle

25 Scopus citations

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-470 130 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.

Original languageEnglish (US)
Pages (from-to)1329-1337
Number of pages9
JournalMolecular Cancer Therapeutics
Volume6
Issue number4
DOIs
StatePublished - Apr 1 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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