Targeting the epidermal growth factor receptor by gefitinib for treatment of hepatocellular carcinoma

被引:162
作者
Höpfner, M
Sutter, AP
Huether, A
Schuppan, D
Zeitz, M
Scherübl, H
机构
[1] Univ Med Berlin, Charite, Med Clin 1, D-12200 Berlin, Germany
[2] Univ Erlangen Nurnberg, Dept Med 1, Erlangen, Germany
关键词
ZD1839; epidermal growth factor receptor; hepatocellular carcinoma; apoptosis; cell cycle; proliferation;
D O I
10.1016/j.jhep.2004.08.024
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background/Aims: Hepatocellular carcinoma (HCC) is one of the most common cancer-related causes of death worldwide. Due to very poor 5-year-survival new therapeutic approaches are mandatory. Gefitinib, an inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR-TK), potently suppresses the growth of various tumors, but its effect on HCC remains unexplored. We therefore studied the antineoplastic potency of gefitinib in human HCC cells. Results: Gefitinib induced a time- and dose-dependent growth inhibition of the human HCC cell lines Huh-7 and HepG2. Gefitinib-treatment induced both mitochondria-dependent and -independent apoptosis. Changes in mitochondrial membrane potential and caspase-8 activation, followed by caspase-3 activation and nuclear degradation, were detected. Moreover, gefitinib induced cell cycle arrest at the G1/S checkpoint and decreased the phosphorylation of mitogen-activated protein kinase ERK1/2. Finally, gefitinib suppressed the expression of antiapoptotic Bcl-2 and Bcl-X-L, further rendering HCC cells prone to apoptosis. Conclusions: Our data demonstrate that the inhibition of EGFR-TK by gefitinib induced growth inhibition, apoptosis and cell cycle arrest in human HCC cells. Thus, EGFR-TK inhibition appears to be a promising novel approach for future treatment strategies of HCC. (C) 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
引用
收藏
页码:1008 / 1016
页数:9
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