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The insulin‐like growth factor‐I receptor inhibitor NVP‐AEW541 provokes cell cycle arrest and apoptosis in multiple myeloma cells
Author(s) -
Maiso Patricia,
Ocio Enrique M.,
Garayoa Mercedes,
Montero Juan C.,
Hofmann Francesco,
GarcíaEcheverría Carlos,
Zimmermann Johann,
Pandiella Atanasio,
San Miguel Jesús F.
Publication year - 2008
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2008.07049.x
Subject(s) - bortezomib , insulin like growth factor , cancer research , growth factor , multiple myeloma , downregulation and upregulation , receptor , medicine , chemistry , biochemistry , gene
Summary 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.