Activity of the selective IκB kinase inhibitor BMS-345541 against T-cell acute lymphoblastic leukemia: Involvement of FOXO3a

Francesca Buontempo, Francesca Chiarini, Daniela Bressanin, Giovanna Tabellini, Fraia Melchionda, Andrea Pession, Milena Fini, Luca M. Neri, James A. McCubrey, Alberto M. Martelli

Research output: Contribution to journalArticle

Abstract

Several lines of evidence suggest that the IκB kinase (IKK)/nuclear factorκB (NFκB) axis is required for viability of leukemic cells and is a predictor of relapse in T-cell acute lymphoblastic leukemia (T-ALL). Moreover, many anticancer agents induce NFκB nuclear translocation and activation of its target genes, which counteract cellular resistance to chemotherapeutic drugs. Therefore, the design and the study of IKK-specific drugs is crucial to inhibit tumor cell proliferation and to prevent cancer drug-resistance. Here, we report the anti-proliferative effects induced by BMS-345541 (a highly selective IKK inhibitor) in three Notch1-mutated T-ALL cell lines and in T-ALL primary cells from pediatric patients. BMS-345541 induced apoptosis and an accumulation of cells in the G2/M phase of the cell cycle via inhibition of IKK/NFκB signaling. We also report that T-ALL cells treated with BMS-345541 displayed nuclear translocation of FOXO3a and restoration of its functions, including control of p21Cip1 expression levels. We demonstrated that FOXO3a subcellular re-distribution is independent of AKT and ERK 1/2 signaling, speculating that in T-ALL the loss of FOXO3a tumor suppressor function could be due to deregulation of IKK, as has been previously demonstrated in other cancer types. It is well known that, differently from p53, FOXO3a mutations have not yet been found in human tumors, which makes therapeutics activating FOXO3a more appealing than others. For these features, BMS-345541 could be used alone or in combination with traditional therapies in the treatment of T-ALL.

Original languageEnglish
Pages (from-to)2467-2475
Number of pages9
JournalCell Cycle
Volume11
Issue number13
DOIs
Publication statusPublished - Jul 1 2012

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Keywords

  • Apoptosis
  • BMS-345541
  • Cell cycle
  • FOXO3a
  • IKK
  • NFκB
  • T-cell acute lymphoblastic leukemia

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Cite this

Buontempo, F., Chiarini, F., Bressanin, D., Tabellini, G., Melchionda, F., Pession, A., Fini, M., Neri, L. M., McCubrey, J. A., & Martelli, A. M. (2012). Activity of the selective IκB kinase inhibitor BMS-345541 against T-cell acute lymphoblastic leukemia: Involvement of FOXO3a. Cell Cycle, 11(13), 2467-2475. https://doi.org/10.4161/cc.20859