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The insulin-like growth factor-I receptor inhibitor NVP-AEW541 provokes cell cycle arrest and apoptosis in multiple myeloma cells.
Br J Haematol. 2008 May; 141(4):470-82.BJ

Abstract

Multiple myeloma (MM) is a B-cell malignancy characterized by accumulation of monoclonal plasma cells in the bone marrow (BM). Despite recent advances in the treatment, MM represents an incurable disease for which development of new therapies is required. We report the antimyeloma effect of NVP-AEW541, a small molecule that belongs to the pyrrolo[2,3-d]pyrimidine class, identified as a selective inhibitor of the insulin-like growth factor-I receptor (IGF-IR) in vitro kinase activity. NVP-AEW541 had a potent cytotoxic effect on fresh cells and in a murine MM model. NVP-AEW541 partially abrogated the proliferative advantage conferred by the coculture with BM stromal cells and the presence of growth factors produced by the BM microenvironment. In addition, NVP-AEW541 potentiated the action of drugs, such as bortezomib, lenalidomide, dexamethasone or melphalan. Moreover the triple combination of NVP-AEW541, dexamethasone and bortezomib resulted in a significant increase in growth inhibition. Mechanistic studies indicated that NVP-AEW541 provoked a marked cell cycle blockade accompanied by pRb downregulation. Interestingly, NVP-AEW541 increased the levels of p27 associated with a reduction in the CDK2 activity. Finally, NVP-AEW541 induced cell death through caspase-dependent and -independent mechanisms. All these data, suggest the potential effect of IGF-IR kinase inhibitors as therapeutic agents for MM patients.

Authors+Show Affiliations

Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Spain.No 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

18341634

Citation

Maiso, Patricia, et al. "The Insulin-like Growth factor-I Receptor Inhibitor NVP-AEW541 Provokes Cell Cycle Arrest and Apoptosis in Multiple Myeloma Cells." British Journal of Haematology, vol. 141, no. 4, 2008, pp. 470-82.
Maiso P, Ocio EM, Garayoa M, et al. The insulin-like growth factor-I receptor inhibitor NVP-AEW541 provokes cell cycle arrest and apoptosis in multiple myeloma cells. Br J Haematol. 2008;141(4):470-82.
Maiso, P., Ocio, E. M., Garayoa, M., Montero, J. C., Hofmann, F., García-Echeverría, C., Zimmermann, J., Pandiella, A., & San Miguel, J. F. (2008). The insulin-like growth factor-I receptor inhibitor NVP-AEW541 provokes cell cycle arrest and apoptosis in multiple myeloma cells. British Journal of Haematology, 141(4), 470-82. https://doi.org/10.1111/j.1365-2141.2008.07049.x
Maiso P, et al. The Insulin-like Growth factor-I Receptor Inhibitor NVP-AEW541 Provokes Cell Cycle Arrest and Apoptosis in Multiple Myeloma Cells. Br J Haematol. 2008;141(4):470-82. PubMed PMID: 18341634.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The insulin-like growth factor-I receptor inhibitor NVP-AEW541 provokes cell cycle arrest and apoptosis in multiple myeloma cells. AU - Maiso,Patricia, AU - Ocio,Enrique M, AU - Garayoa,Mercedes, AU - Montero,Juan C, AU - Hofmann,Francesco, AU - García-Echeverría,Carlos, AU - Zimmermann,Johann, AU - Pandiella,Atanasio, AU - San Miguel,Jesús F, Y1 - 2008/03/12/ PY - 2008/3/18/pubmed PY - 2008/7/4/medline PY - 2008/3/18/entrez SP - 470 EP - 82 JF - British journal of haematology JO - Br J Haematol VL - 141 IS - 4 N2 - Multiple myeloma (MM) is a B-cell malignancy characterized by accumulation of monoclonal plasma cells in the bone marrow (BM). Despite recent advances in the treatment, MM represents an incurable disease for which development of new therapies is required. We report the antimyeloma effect of NVP-AEW541, a small molecule that belongs to the pyrrolo[2,3-d]pyrimidine class, identified as a selective inhibitor of the insulin-like growth factor-I receptor (IGF-IR) in vitro kinase activity. NVP-AEW541 had a potent cytotoxic effect on fresh cells and in a murine MM model. NVP-AEW541 partially abrogated the proliferative advantage conferred by the coculture with BM stromal cells and the presence of growth factors produced by the BM microenvironment. In addition, NVP-AEW541 potentiated the action of drugs, such as bortezomib, lenalidomide, dexamethasone or melphalan. Moreover the triple combination of NVP-AEW541, dexamethasone and bortezomib resulted in a significant increase in growth inhibition. Mechanistic studies indicated that NVP-AEW541 provoked a marked cell cycle blockade accompanied by pRb downregulation. Interestingly, NVP-AEW541 increased the levels of p27 associated with a reduction in the CDK2 activity. Finally, NVP-AEW541 induced cell death through caspase-dependent and -independent mechanisms. All these data, suggest the potential effect of IGF-IR kinase inhibitors as therapeutic agents for MM patients. SN - 1365-2141 UR - https://www.unboundmedicine.com/medline/citation/18341634/The_insulin_like_growth_factor_I_receptor_inhibitor_NVP_AEW541_provokes_cell_cycle_arrest_and_apoptosis_in_multiple_myeloma_cells_ L2 - https://doi.org/10.1111/j.1365-2141.2008.07049.x DB - PRIME DP - Unbound Medicine ER -