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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
Author(s) -
Xiao Xia,
Wu Jiangxue,
Zhu Xiaofeng,
Zhao Peng,
Zhou Jinlin,
Liu Quentin Qiang,
Zheng Limin,
Zeng Musheng,
Liu Ranyi,
Huang Wenlin
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22955
Subject(s) - cancer research , nasopharyngeal carcinoma , apoptosis , tyrosine kinase , cell growth , cell cycle checkpoint , epidermal growth factor , biology , receptor tyrosine kinase , in vivo , cell cycle , epidermal growth factor receptor , cell culture , kinase , medicine , signal transduction , microbiology and biotechnology , receptor , biochemistry , radiation therapy , genetics
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‐X L , 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.