title: 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.
abstract: 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.
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, People's Republic of China.
authors.forename: Xia
authors.initials: X
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, People's Republic of China.
authors.forename: Jiangxue
authors.initials: J
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, People's Republic of China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, People's Republic of China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, People's Republic of China.
authors.forename: Jinlin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, People's Republic of China.
authors.forename: Quentin Qiang
authors.initials: QQ
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, People's Republic of China.
authors.forename: Limin
authors.initials: L
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, People's Republic of China.
authors.forename: Musheng
authors.initials: M
authors.lastname: Zeng
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, People's Republic of China.
authors.forename: Ranyi
authors.initials: R
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, People's Republic of China.|Institute of Microbiology, Chinese Academy of Science, Beijing 100080, People's Republic of China.|Guangzhou Doublle Bio-product Inc., Guangzhou 516003, People's Republic of China.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009303:Nasopharyngeal Neoplasms / Q000201:enzymology* / Q000473:pathology*; D010880:Piperidines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; C452423:vandetanib