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Molecular Targets for Therapy

The insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 induces apoptosis in acute myeloid leukemia cells exhibiting autocrine insulin-like growth factor-I secretion

Leukemia volume 21, pages 886–896 (2007)Cite this article

Abstract

Insulin-like growth factor-I (IGF-I) and its receptor (IGF-IR) have been implicated in the pathophysiology of many human cancers, including those of hematopoietic lineage. We investigated the therapeutic potential of the novel IGF-IR tyrosine kinase activity inhibitor, NVP-AEW541, on human acute myeloid leukemia (AML) cells. NVP-AEW541 was tested on a HL60 cell subclone, which is dependent on autocrine secretion of IGF-I for survival and drug resistance, as well as primary drug resistant leukemia cells. NVP-AEW541 treatment (24 h) induced dephosphorylation of IGF-IR. NVP-AEW541 also caused Akt dephosphorylation and changes in the expression of key regulatory proteins of the cell cycle. At longer incubation times (48 h), NVP-AEW541-induced apoptotic cell death, as demonstrated by caspase-3 cleavage. Apoptosis was accompanied by decreased expression of anti-apoptotic proteins. NVP-AEW541 enhanced sensitivity of HL60 cells to either cytarabine or etoposide. Moreover, NVP-AEW541 reduced the clonogenic capacity of AML CD34+ cells cultured in the presence of IGF-I. Chemoresistant AML blasts displayed enhanced IGF-I secretion, and were sensitized to etoposide-induced apoptosis by NVP-AEW541. Our findings indicate that NVP-AEW541 might be a promising therapeutic agent for the treatment of those AML cases characterized by IGF-I autocrine secretion.

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Acknowledgements

This work was supported by grants from: Fondazione CARISBO, Associazione Italiana Ricerca sul Cancro (AIRC Regional grants), Italian MUR PRIN 2005. JAM was supported by the USA Public Health Service (RO1098195).

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Authors and Affiliations

  1. Servizio di Immunoematologia e Trasfusionale, Policlinico S.Orsola-Malpighi, Bologna, Italy

    P L Tazzari

  2. Dipartimento di Scienze Biomediche e Biotecnologie, Sezione di Citologia e Istologia, Università di Brescia, Brescia, Italy

    G Tabellini

  3. Dipartimento di Biomedicina, Università di Trieste, Trieste, Italy

    R Bortul

  4. Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Università di Bologna, Bologna, Italy

    V Papa, C Evangelisti & A M Martelli

  5. Istituto di Ematologia ed Oncologia Medica Seràgnoli, Università di Bologna, Bologna, Italy

    T Grafone & G Martinelli

  6. Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA

    J A McCubrey

  7. IGM-CNR, Sezione di Bologna c/o I.O.R., Bologna, Italy

    A M Martelli

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Tazzari, P., Tabellini, G., Bortul, R. et al. The insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 induces apoptosis in acute myeloid leukemia cells exhibiting autocrine insulin-like growth factor-I secretion. Leukemia 21, 886–896 (2007). https://doi.org/10.1038/sj.leu.2404643

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