| Sensitivity of breast cancer cell lines to the novel insulin-like growth factor-1 receptor (IGF-1R) inhibitor NVP-AEW541 is dependent on the level of IRS-1 expression. | |
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MedLine Citation:
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PMID: 19345478 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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To investigate the potential value of targeting insulin-like growth factor-1 receptor (IGF-1R) in breast cancer, we examined the effects of NVP-AEW541, a selective small-molecule inhibitor of the IGF-1R tyrosine kinase, in a panel of 16 breast cancer cell lines. All cell lines expressed IGF-1R, but MCF-7 expressed much higher levels of insulin receptor substrate-1 (IRS-1) than the others. NVP-AEW541 was more potent at inhibiting growth of MCF-7 cells as compared to the others (IC(50), 1 microM vs. approximately 7 microM). Comparing MCF-7 to T47D cells, which express IGF-1R at a level identical to MCF-7 but have less than 1/30 the amount of IRS-1, NVP-AEW541 caused cell-cycle arrest at the G1-S boundary, reduced in vitro cell migration, and enhanced the cytotoxic effects of vinorelbine and paclitaxel in MCF-7, but not in T47D. While NVP-AEW541 decreased the phosphorylation of IGF-1R in both cell lines, it inhibited phosphorylation of Akt and disrupted the IRS-1/PI3K complex only in MCF-7. These findings suggest that inhibiting IGF-1R may be an effective therapeutic strategy for breast cancers that co-express IGF-1R and IRS-1 at high levels. |
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Authors:
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Toru Mukohara; Hiroyuki Shimada; Naomi Ogasawara; Ryoko Wanikawa; Manami Shimomura; Tetsuya Nakatsura; Genichiro Ishii; Joon Oh Park; Pasi A Jänne; Nagahiro Saijo; Hironobu Minami |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-04-03 |
Journal Detail:
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Title: Cancer letters Volume: 282 ISSN: 1872-7980 ISO Abbreviation: Cancer Lett. Publication Date: 2009 Sep |
Date Detail:
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Created Date: 2009-07-06 Completed Date: 2009-07-31 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 7600053 Medline TA: Cancer Lett Country: Ireland |
Other Details:
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Languages: eng Pagination: 14-24 Citation Subset: IM |
Affiliation:
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Division of Oncology and Hematology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Japan. mukohara@med.kobe-u.ac.jp |
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| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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therapeutic use* Blotting, Western Breast Neoplasms / drug therapy*, pathology* Cell Division / drug effects Cell Line, Tumor Enzyme Inhibitors / therapeutic use Humans Insulin Receptor Substrate Proteins / genetics, metabolism Phosphorylation Protein-Tyrosine Kinases / antagonists & inhibitors Pyrimidines / therapeutic use* Pyrroles / therapeutic use* Receptor Protein-Tyrosine Kinases / drug effects, metabolism Receptor, IGF Type 1 / genetics, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Enzyme Inhibitors; 0/IRS1 protein, human; 0/Insulin Receptor Substrate Proteins; 0/NVP-AEW541; 0/Pyrimidines; 0/Pyrroles; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.10.1/Receptor Protein-Tyrosine Kinases; EC 2.7.10.1/Receptor, IGF Type 1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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