TY - JOUR
T1 - Tumor cytotoxicity and endothelial Rac inhibition induced by TNP-470 in anaplastic thyroid cancer
AU - Nahari, Dorit
AU - Satchi-Fainaro, Ronit
AU - Chen, Ming
AU - Mitchell, Ian
AU - Task, Laurie B.
AU - Liu, Zijuan
AU - Kihneman, Jason
AU - Carroll, Allison B.
AU - Terada, Lance S.
AU - Nwariaku, Fiemu E.
PY - 2007/4
Y1 - 2007/4
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-06-0554
DO - 10.1158/1535-7163.MCT-06-0554
M3 - Article
C2 - 17431111
AN - SCOPUS:34248159493
SN - 1535-7163
VL - 6
SP - 1329
EP - 1337
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 4
ER -