Effect of PTK/ZK on the angiogenic switch in head and neck tumors.
Transformation of small avascular masses of tumor cells into rapidly progressive cancers is triggered by the angiogenic switch, a process that involves vascular endothelial growth factor (VEGF) signaling. We have shown that VEGF enhances the survival and angiogenic potential of endothelial cells by activating the Bcl-2-CXCL8 signaling axis. The purpose of this study was to evaluate the effect of a small-molecule inhibitor of VEGF receptors (PTK/ZK) on the initial stages of head and neck tumor angiogenesis. In vitro, PTK/ZK blocked head and neck tumor cell (OSCC3 or UM-SCC-17B)-induced Bcl-2 and CXCL8 expression in endothelial cells. Oral administration of PTK/ZK decreased xenograft head and neck tumor microvessel density, and inhibited Bcl-2 and CXCL8 expression in tumor-associated endothelial cells. Analysis of these data demonstrates that PTK/ZK blocks downstream targets of VEGF signaling in endothelial cells, and suggests that PTK/ZK may inhibit the angiogenic switch in head and neck tumors.
Miyazawa
M
M
Department of Cariology, Restorative Sciences, and Endodontics, University of Michigan School of Dentistry, 1011 N. University, Ann Arbor, MI 48109-1078, USA.
Dong
Z
Z
Zhang
Z
Z
Neiva
K G
KG
Cordeiro
M M
MM
Oliveira
D T
DT
Nör
J E
JE
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000098:blood supply*; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors; D051379:Mice; D016513:Mice, SCID; D055806:Microvessels / Q000187:drug effects; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology*; D010793:Phthalazines / Q000008:administration & dosage / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D016209:Interleukin-8; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; C404768:vatalanib; D040262:Receptors, Vascular Endothelial Growth Factor