Effect of PTK/ZK on the Angiogenic Switch in Head and Neck Tumors

• Published in: Journal of dental research 2008-12, Vol.87 (12), p.1166-1171
• Main Authors: Miyazawa, M., Dong, Z., Zhang, Z., Neiva, K.G., Cordeiro, M.M., Oliveira, D.T., Nör, J.E.
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - pharmacology; Animals; Carcinoma, Squamous Cell - blood supply; Cell Line, Tumor; Coculture Techniques; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelial Cells - drug effects; Endothelium, Vascular - drug effects; Head and Neck Neoplasms - blood supply; Humans; Interleukin-8 - antagonists & inhibitors; Mice; Mice, SCID; Microvessels - drug effects; Neoplasm Transplantation; Neovascularization, Pathologic - pathology; Phthalazines - administration & dosage; Phthalazines - pharmacology; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Pyridines - administration & dosage; Pyridines - pharmacology; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; Transplantation, Heterologous; Tumor Cells, Cultured
• ISSN: 0022-0345; 1544-0591
• DOI: 10.1177/154405910808701213

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. Abbreviations: HDMEC, human dermal microvascular endothelial cells; VEGF, vascular endothelial growth factor; CXCL8, CXC ligand-8; PTK/ZK, PTK787/ZK222584.