Tumor cytotoxicity and endothelial Rac inhibition induced by TNP-470 in anaplastic thyroid cancer.
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.
Nahari
Dorit
D
Department of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9156, USA.
Satchi-Fainaro
Ronit
R
Chen
Ming
M
Mitchell
Ian
I
Task
Laurie B
LB
Liu
Zijuan
Z
Kihneman
Jason
J
Carroll
Allison B
AB
Terada
Lance S
LS
Nwariaku
Fiemu E
FE
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D022081:Cell Surface Extensions / Q000187:drug effects; D003510:Cyclohexanes / Q000494:pharmacology* / Q000627:therapeutic use; D003599:Cytoskeleton / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D017629:Gap Junctions / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012717:Sesquiterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D016019:Survival Analysis; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors*
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; D020744:rac GTP-Binding Proteins; D000077609:O-(Chloroacetylcarbamoyl)fumagillol