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
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
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DOI：
10.1002/ijc.22955
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发表时间：
2007-11-01
影响因子：
6.4
通讯作者：
Huang, Wenlin
中科院分区：
文献类型：
--
作者：
Xiao, Xia;Wu, Jiangxue;Huang, Wenlin
ZD6474 是一种血管内皮生长因子受体 (VEGFR) 和表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂。本研究旨在探讨 ZD6474 在体外对人鼻咽癌 (NPC) 的直接抗增殖作用以及在体内对 NPC 异种移植物的抗肿瘤活性。结果表明，ZD6474 治疗抑制 EGFR 磷酸化，导致 NPC 细胞（CNE-1、CNE-2 和 C666-1）增殖呈剂量和时间依赖性下降。进一步研究表明，所有 3 个细胞系均出现 G0/G1 细胞周期停滞，这与 p21 和/或 p27 的上调以及 CDK4、CDK6 和 CDK2 的下调有关。 ZD6474 治疗还诱导 CNE-1 和 CNE-2 细胞凋亡。细胞凋亡机制涉及Bcl-2和/或Bcl-X-L的减少、Bak和/或Bax的诱导以及caspases-3、-9和/或-8的激活。在CNE-2和C666-1异种移植裸鼠中评价体内抗肿瘤活性。在两种模型中，给予 ZD6474（25100 mg/kg/天，每日一次，口服）可产生剂量依赖性的肿瘤生长抑制并延长生存期。这项研究表明，ZD6474 通过诱导 G0/G1 期停滞和细胞凋亡，在体外对鼻咽癌细胞系发挥直接的抗增殖作用，并在体内对鼻咽癌异种移植物产生有效的抗肿瘤作用。这表明ZD6474可能为人类鼻咽癌提供一种新的有效治疗方法。 (C) 2007 Wiley-Liss, Inc.
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 (25100 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. (C) 2007 Wiley-Liss, Inc.