Induction of cell cycle arrest and apoptosis in human nasopharyngeal carcinoma cells by ZD6474, an inhibitor of VEGFR tyrosine kinase with additional activity against EGFR tyrosine kinase

• Published in: International journal of cancer 2007-11, Vol.121 (9), p.2095-2104
• Main Authors: Xiao, Xia, Wu, Jiangxue, Zhu, Xiaofeng, Zhao, Peng, Zhou, Jinlin, Liu, Quentin Qiang, Zheng, Limin, Zeng, Musheng, Liu, Ranyi, Huang, Wenlin
• Format: Article
• Language: English
• Subjects: Animals; apoptosis; Apoptosis - drug effects; Biological and medical sciences; cell cycle; Cell Cycle - drug effects; Cell Line, Tumor; epidermal growth factor receptor; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - metabolism; Female; Humans; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; nasopharyngeal carcinoma; Nasopharyngeal Neoplasms - enzymology; Nasopharyngeal Neoplasms - pathology; Otorhinolaryngology. Stomatology; Piperidines - pharmacology; Protein Kinase Inhibitors - pharmacology; Quinazolines - pharmacology; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; Receptors, Vascular Endothelial Growth Factor - metabolism; Signal Transduction; Survival Rate; Tumors; tyrosine kinase inhibitor; Upper respiratory tract, upper alimentary tract, paranasal sinuses, salivary glands: diseases, semeiology; vascular endothelial growth factor receptor; Xenograft Model Antitumor Assays; ZD6474
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.22955

ZD6474 is a vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. The present study was undertaken to investigate the direct antiproliferative effect of ZD6474 on human nasopharyngeal carcinoma (NPC) in vitro and the antitumor activity on NPC xenografts in vivo. Results indicated that ZD6474 treatment inhibited EGFR phosphorylation and led to a dose‐ and time‐dependent decrease in NPC cell (CNE‐1, CNE‐2 and C666‐1) proliferation. Further investigation demonstrated G0/G1 cell cycle arrest in all 3 cell lines, which was associated with an upregulation of p21 and/or p27, and downregulation of CDK4, CDK6 and CDK2. ZD6474 treatment also induced apoptosis in CNE‐1 and CNE‐2 cells. The apoptosis mechanisms involved reduction of Bcl‐2 and/or Bcl‐XL, induction of Bak and/or Bax, and activation of caspases‐3, ‐9 and/or ‐8. The in vivo antitumor activity was evaluated in CNE‐2 and C666‐1 xenografted nude mice. Administration of ZD6474 (25–100 mg/kg/day, once‐daily, p.o.) produced a dose‐dependent inhibition of tumor growth and prolonged survival in both models. This study suggests that ZD6474 exerts direct antiproliferative effects on NPC cell lines in vitro by inducing G0/G1 arrest and apoptosis, and potent antitumor effects on NPC xenografts in vivo. It indicates that ZD6474 may offer a new and effective treatment for human NPC. © 2007 Wiley‐Liss, Inc.