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Tyrosine kinase of insulin-like growth factor receptor as target for novel treatment and prevention strategies of colorectal cancer.
- Source :
-
World journal of gastroenterology [World J Gastroenterol] 2006 Sep 21; Vol. 12 (35), pp. 5635-43. - Publication Year :
- 2006
-
Abstract
- 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).<br />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.<br />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(Kip1), 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.<br />Conclusion: IGF-1R-TK inhibition is a promising novel approach for either mono- or combination treatment strategies of colorectal carcinoma and even for CRC chemoprevention.
- Subjects :
- Adenocarcinoma metabolism
Adenocarcinoma pathology
Antibodies, Monoclonal therapeutic use
Antibodies, Monoclonal, Humanized
Antineoplastic Agents therapeutic use
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Apoptosis drug effects
Cell Cycle drug effects
Cell Line, Tumor
Cetuximab
Colorectal Neoplasms metabolism
Colorectal Neoplasms pathology
Cytotoxins therapeutic use
Dose-Response Relationship, Drug
Fatty Acids, Monounsaturated therapeutic use
Fluvastatin
Gene Expression Regulation, Neoplastic drug effects
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use
Indoles therapeutic use
L-Lactate Dehydrogenase genetics
L-Lactate Dehydrogenase metabolism
Pyrimidines therapeutic use
Pyrroles therapeutic use
Receptor Protein-Tyrosine Kinases antagonists & inhibitors
Receptor Protein-Tyrosine Kinases genetics
Receptor Protein-Tyrosine Kinases metabolism
Receptor, IGF Type 1 antagonists & inhibitors
Receptor, IGF Type 1 genetics
Receptor, IGF Type 1 metabolism
Adenocarcinoma drug therapy
Adenocarcinoma prevention & control
Colorectal Neoplasms drug therapy
Colorectal Neoplasms prevention & control
Pyrimidines pharmacology
Pyrroles pharmacology
Receptor Protein-Tyrosine Kinases drug effects
Receptor, IGF Type 1 drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1007-9327
- Volume :
- 12
- Issue :
- 35
- Database :
- MEDLINE
- Journal :
- World journal of gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 17007015
- Full Text :
- https://doi.org/10.3748/wjg.v12.i35.5635