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

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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 2007

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Neoplasms
Vascular Endothelial Growth Factor A
Endothelial Cells
Anaplastic Thyroid Carcinoma
O-(chloroacetylcarbamoyl)fumagillol
Angiogenesis Inhibitors
Survival
Microvessels
Thyroid Neoplasms
Nude Mice
Permeability
Thyroid Gland
Animal Models
Neoplasm Metastasis
Liver
In Vitro Techniques

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

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Tumor cytotoxicity and endothelial Rac inhibition induced by TNP-470 in anaplastic thyroid cancer. / Nahari, Dorit; Satchi-Fainaro, Ronit; Chen, Ming; Mitchell, Ian; Task, Laurie B.; Liu, Zijuan; Kihneman, Jason; Carroll, Allison B.; Terada, Lance S.; Nwariaku, Fiemu E.

In: Molecular Cancer Therapeutics, Vol. 6, No. 4, 04.2007, p. 1329-1337.

Research output: Contribution to journalArticle

Nahari, D, Satchi-Fainaro, R, Chen, M, Mitchell, I, Task, LB, Liu, Z, Kihneman, J, Carroll, AB, Terada, LS & Nwariaku, FE 2007, 'Tumor cytotoxicity and endothelial Rac inhibition induced by TNP-470 in anaplastic thyroid cancer', Molecular Cancer Therapeutics, vol. 6, no. 4, pp. 1329-1337. https://doi.org/10.1158/1535-7163.MCT-06-0554
Nahari, Dorit ; Satchi-Fainaro, Ronit ; Chen, Ming ; Mitchell, Ian ; Task, Laurie B. ; Liu, Zijuan ; Kihneman, Jason ; Carroll, Allison B. ; Terada, Lance S. ; Nwariaku, Fiemu E. / Tumor cytotoxicity and endothelial Rac inhibition induced by TNP-470 in anaplastic thyroid cancer. In: Molecular Cancer Therapeutics. 2007 ; Vol. 6, No. 4. pp. 1329-1337.
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