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Inhibition of insulin-like growth factor-1 receptor signaling enhances growth-inhibitory and proapoptotic effects of gefitinib (Iressa) in human breast cancer cells.
Breast Cancer Res. 2005; 7(4):R570-9.BC

Abstract

INTRODUCTION

Gefitinib (Iressa, ZD 1839, AstraZeneca) blocks the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and inhibits proliferation of several human cancer cell types including breast cancer. Phase II clinical trials with gefitinib monotherapy showed an objective response of 9 to 19% in non-small-cell lung cancer patients and less than 10% for breast cancer, and phase III results have indicated no benefit of gefitinib in combination with chemotherapy over chemotherapy alone. In order to improve the antineoplastic activity of gefitinib, we investigated the effects of blocking the signalling of the insulin-like growth factor 1 receptor (IGF-1R), a tyrosine kinase with a crucial role in malignancy that is coexpressed with EGFR in most human primary breast carcinomas.

METHODS

AG1024 (an inhibitor of IGF-1R) was used with gefitinib for treatment of MDA468, MDA231, SK-BR-3, and MCF-7 breast cancer lines, which express similar levels of IGF-1R but varying levels of EGFR. Proliferation assays, apoptosis induction studies, and Western blot analyses were conducted with cells treated with AG1024 and gefitinib as single agents and in combination.

RESULTS

Gefitinib and AG1024 reduced proliferation in all lines when used as single agents, and when used in combination revealed an additive-to-synergistic effect on cell growth inhibition. Flow cytometry measurements of cells stained with annexin V-propidium iodide and cells stained for caspase-3 activation indicated that adding an IGF-1R-targeting strategy to gefitinib results in higher levels of apoptosis than are achieved with gefitinib alone. Gefitinib either reduced or completely inhibited p42/p44 Erk kinase phosphorylation, depending on the cell line, while Akt phosphorylation was reduced by a combination of the two agents. Overexpression of IGF-1R in SK-BR-3 cells was sufficient to cause a marked enhancement in gefitinib resistance.

CONCLUSION

These results indicate that IGF-1R signaling reduces the antiproliferative effects of gefitinib in several breast cancer cell lines, and that the addition of an anti-IGF-1R strategy to gefitinib treatment may be more effective than a single-agent approach.

Authors+Show Affiliations

Lady Davis Institute for Medical Research, Department of Oncology, McGill University, Montréal, QC, Canada. anne.camirand@mail.mcgill.caNo 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

15987464

Citation

Camirand, Anne, et al. "Inhibition of Insulin-like Growth Factor-1 Receptor Signaling Enhances Growth-inhibitory and Proapoptotic Effects of Gefitinib (Iressa) in Human Breast Cancer Cells." Breast Cancer Research : BCR, vol. 7, no. 4, 2005, pp. R570-9.
Camirand A, Zakikhani M, Young F, et al. Inhibition of insulin-like growth factor-1 receptor signaling enhances growth-inhibitory and proapoptotic effects of gefitinib (Iressa) in human breast cancer cells. Breast Cancer Res. 2005;7(4):R570-9.
Camirand, A., Zakikhani, M., Young, F., & Pollak, M. (2005). Inhibition of insulin-like growth factor-1 receptor signaling enhances growth-inhibitory and proapoptotic effects of gefitinib (Iressa) in human breast cancer cells. Breast Cancer Research : BCR, 7(4), R570-9.
Camirand A, et al. Inhibition of Insulin-like Growth Factor-1 Receptor Signaling Enhances Growth-inhibitory and Proapoptotic Effects of Gefitinib (Iressa) in Human Breast Cancer Cells. Breast Cancer Res. 2005;7(4):R570-9. PubMed PMID: 15987464.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of insulin-like growth factor-1 receptor signaling enhances growth-inhibitory and proapoptotic effects of gefitinib (Iressa) in human breast cancer cells. AU - Camirand,Anne, AU - Zakikhani,Mahvash, AU - Young,Fiona, AU - Pollak,Michael, Y1 - 2005/04/12/ PY - 2004/11/10/received PY - 2005/02/23/revised PY - 2005/03/18/accepted PY - 2005/7/1/pubmed PY - 2006/1/26/medline PY - 2005/7/1/entrez SP - R570 EP - 9 JF - Breast cancer research : BCR JO - Breast Cancer Res VL - 7 IS - 4 N2 - INTRODUCTION: Gefitinib (Iressa, ZD 1839, AstraZeneca) blocks the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and inhibits proliferation of several human cancer cell types including breast cancer. Phase II clinical trials with gefitinib monotherapy showed an objective response of 9 to 19% in non-small-cell lung cancer patients and less than 10% for breast cancer, and phase III results have indicated no benefit of gefitinib in combination with chemotherapy over chemotherapy alone. In order to improve the antineoplastic activity of gefitinib, we investigated the effects of blocking the signalling of the insulin-like growth factor 1 receptor (IGF-1R), a tyrosine kinase with a crucial role in malignancy that is coexpressed with EGFR in most human primary breast carcinomas. METHODS: AG1024 (an inhibitor of IGF-1R) was used with gefitinib for treatment of MDA468, MDA231, SK-BR-3, and MCF-7 breast cancer lines, which express similar levels of IGF-1R but varying levels of EGFR. Proliferation assays, apoptosis induction studies, and Western blot analyses were conducted with cells treated with AG1024 and gefitinib as single agents and in combination. RESULTS: Gefitinib and AG1024 reduced proliferation in all lines when used as single agents, and when used in combination revealed an additive-to-synergistic effect on cell growth inhibition. Flow cytometry measurements of cells stained with annexin V-propidium iodide and cells stained for caspase-3 activation indicated that adding an IGF-1R-targeting strategy to gefitinib results in higher levels of apoptosis than are achieved with gefitinib alone. Gefitinib either reduced or completely inhibited p42/p44 Erk kinase phosphorylation, depending on the cell line, while Akt phosphorylation was reduced by a combination of the two agents. Overexpression of IGF-1R in SK-BR-3 cells was sufficient to cause a marked enhancement in gefitinib resistance. CONCLUSION: These results indicate that IGF-1R signaling reduces the antiproliferative effects of gefitinib in several breast cancer cell lines, and that the addition of an anti-IGF-1R strategy to gefitinib treatment may be more effective than a single-agent approach. SN - 1465-542X UR - https://www.unboundmedicine.com/medline/citation/15987464/Inhibition_of_insulin_like_growth_factor_1_receptor_signaling_enhances_growth_inhibitory_and_proapoptotic_effects_of_gefitinib__Iressa__in_human_breast_cancer_cells_ L2 - https://breast-cancer-research.biomedcentral.com/articles/10.1186/bcr1028 DB - PRIME DP - Unbound Medicine ER -