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Tyrosine kinase of insulin-like growth factor receptor as target for novel treatment and prevention strategies of colorectal cancer 被引量:10

Tyrosine kinase of insulin-like growth factor receptor as target for novel treatment and prevention strategies of colorectal cancer
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摘要 AIM: To investigate the antineoplastic potency of the novel insulin-like growth factor 1 receptor (IGF-1R) tyrosine 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 staining were used for analysis of growth factor receptor protein expression and detection of cell number changes, respectively. Cytotoxicity was determined by measuring the release of the cytoplasmic enzyme lactate dehydrogenase (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 activation 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 p21^waf1/CIP1 and p27^kjp1, and the downregulation of the cell cycle promoter cyclin D1. Moreover, BAX was upregulated 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 observed 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 monoor combination treatment strategies of colorectal carcinoma and even for CRC chemoprevention. 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.
出处 《World Journal of Gastroenterology》 SCIE CAS CSCD 2006年第35期5635-5643,共9页 世界胃肠病学杂志(英文版)
关键词 Insulin-like growth factor receptor Tyrosine kinase Colorectal cancer APOPTOSIS Cell cycle arrest 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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