Blockade of IGF-1 receptor tyrosine kinase has antlineoplastic effects in hepatocellular carcinoma cells

被引:97
作者
Höpfner, M
Huether, A
Sutter, AP
Baradari, V
Schuppan, D
Scheruebl, H [1 ]
机构
[1] Univ Med Berlin, Charite, Med Clin 1, D-12200 Berlin, Germany
[2] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Gastroenterol & Hepatol, Boston, MA USA
关键词
IGF-1; receptor; tyrosine kinase; apoptosis; cell cycle; EGFR; cytostatics;
D O I
10.1016/j.bcp.2006.02.006
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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. Most HCCs express insulin-like growth factors and their receptors (IGF-R). As IGF-1R-mediated signaling promotes survival, oncogenic transformation and tumor growth and spread, it represents a potential target for innovative treatment strategies of HCC. Here we studied the antineoplastic effects of inhibiting IGF-1R signaling in HCC cells by the novel IGF-1R tyrosine kinase inhibitor NVP-AEW541. Methods and results: NVP-AEW541 induced a time- and dose-dependent growth inhibition in the human hepatoblastoma and hepatocellular carcinoma cell lines SK-Hep-1, Hep-3B, Hep-G2 and Huh-7. Measurement of LDH-release showed that the antineoplastic effect of NVP-AEW541 was not due to cytotoxicity. Instead NVP-AEW541 induced apoptosis as evidenced by both caspase-3 and -8 activation as well as by apoptosis-specific morphological and mitochondrial changes. In addition, nuclear degradation was monitored by DNA-laddering. NVP-AEW541-treatment suppressed the expression of the antiapoptotic proteins Bcl-2 and survivin, while the expression of the proapoptotic protein BAX was stimulated in a dose-dependent manner. Moreover, NVP-AEW541 arrested the cell cycle at the G1/S checkpoint. When NVP-AEW541 was combined with cytotoxic chemotherapy or with a specific epidermal growth factor receptor antibody additive antiproliferative effects were observed. Interpretation: Inhibition of IGF-1R tyrosine kinase (IGF-1R-TK) by NVP-AEW541 induces growth inhibition, apoptosis and cell cycle arrest in human HCC cell lines without accompanying cytotoxicity. Thus, IGF-1R-TK inhibition may be a promising novel treatment approach in HCC. (c) 2006 Elsevier Inc. All rights reserved.
引用
收藏
页码:1435 / 1448
页数:14
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