Tyrosine kinase of insulin-like growth factor receptor as target for novel treatment and prevention strategies of colorectal cancer

查看全文 作　　者：Michael H[1]pfner;Andreas P [1]Sutter;Alexander [1]Huether;Viola [1]Baradari;Hans [2]Scherübl

机构地区：[1]Charité-Universittsmedizin Berlin, Campus Benjamin Franklin, Medical Clinic I, Gastroenterology/Infectious Diseases/ Rheumatology, Berlin, Germany;[2]Klinik für Gastroenterologie und Gastrointestinale Onkologie, Vivantes-Klinikum Am Urban, Dieffenbachstr. 1, Berlin 10967, Germany

出　　处：《World Journal of Gastroenterology》索引2006年第12卷第35期,共9页

摘　　要：AIM: To investigate the antineoplastic potency of the novel insulin-like growth factor 1 receptor (IGF-1R) tyro- sine kinase inhibitor (TKI) NVP-AEW541 in cell lines and primary cell cultures of human colorectal cancer (CRC). METHODS: Cells of primary colorectal carcinomas were from 8 patients. Immunostaining and crystal violet stain- ing were used for analysis of growth factor receptor pro- tein expression and detection of cell number changes, respectively. Cytotoxicity was determined by measuring the release of the cytoplasmic enzyme lactate dehydro- genase (LDH). The proportion of apoptotic cells was determined by quantifying the percentage of sub-G1 (hypodiploid) cells. Cell cycle status reflected by the DNA content of the nuclei was detected by flow cytometry. RESULTS: NVP-AEW541 dose-dependently inhibited the proliferation of colorectal carcinoma cell lines and primary cell cultures by inducing apoptosis and cell cycle arrest. Apoptosis was characterized by caspase-3 activa- tion and nuclear degradation. Cell cycle was arrested at the G1/S checkpoint. The NVP-AEW541-mediated cell cycle-related signaling involved the inactivation of Akt and extracellular signal-regulated kinase (ERK) 1/2, the upregulation of the cyclin-dependent kinase inhibitors p21Waf1/CIP1 and p27Kip1, and the downregulation of the cell cycle promoter cyclin D1. Moreover, BAX was upregu- lated during NVP-AEW541-induced apoptosis, whereas Bcl-2 was downregulated. Measurement of LDH release showed that the antineoplastic effect of NVP-AEW541 was not due to general cytotoxicity of the compound. However, augmented antineoplastic effects were ob-served in combination treatments of NVP-AEW541 with either 5-FU, or the EGFR-antibody cetuximab, or the HMG-CoA-reductase inhibitor fluvastatin. CONCLUSION: IGF-1R-TK inhibition is a promising novel approach for either mono- or combination treatment strategies of colorectal carcinoma and even for CRC che- moprevention. 关键词：酪氨酸激酶胰岛素样生长因子治疗结肠癌直肠癌

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Tyrosine kinase of insulin-like growth factor receptor as target for novel treatment and prevention strategies of colorectal cancer

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