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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.
Cancer Lett. 2009 Sep 08; 282(1):14-24.CL

Abstract

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.

Authors+Show Affiliations

Division of Oncology and Hematology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Japan. mukohara@med.kobe-u.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19345478

Citation

Mukohara, Toru, et al. "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." Cancer Letters, vol. 282, no. 1, 2009, pp. 14-24.
Mukohara T, Shimada H, Ogasawara N, et al. 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. Cancer Lett. 2009;282(1):14-24.
Mukohara, T., Shimada, H., Ogasawara, N., Wanikawa, R., Shimomura, M., Nakatsura, T., Ishii, G., Park, J. O., Jänne, P. A., Saijo, N., & Minami, H. (2009). 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. Cancer Letters, 282(1), 14-24. https://doi.org/10.1016/j.canlet.2009.02.056
Mukohara T, et al. 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. Cancer Lett. 2009 Sep 8;282(1):14-24. PubMed PMID: 19345478.
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TY - JOUR T1 - 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. AU - Mukohara,Toru, AU - Shimada,Hiroyuki, AU - Ogasawara,Naomi, AU - Wanikawa,Ryoko, AU - Shimomura,Manami, AU - Nakatsura,Tetsuya, AU - Ishii,Genichiro, AU - Park,Joon Oh, AU - Jänne,Pasi A, AU - Saijo,Nagahiro, AU - Minami,Hironobu, Y1 - 2009/04/03/ PY - 2008/06/03/received PY - 2008/11/27/revised PY - 2009/02/25/accepted PY - 2009/4/7/entrez PY - 2009/4/7/pubmed PY - 2009/8/1/medline SP - 14 EP - 24 JF - Cancer letters JO - Cancer Lett VL - 282 IS - 1 N2 - 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. SN - 1872-7980 UR - https://www.unboundmedicine.com/medline/citation/19345478/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0304-3835(09)00163-3 DB - PRIME DP - Unbound Medicine ER -