Several lines of evidence suggest that the I kappa B kinase (IKK)/nuclear factor kappa B (NF kappa B) 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 NF kappa B 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 G(2)/M phase of the cell cycle via inhibition of IKK/NF kappa B 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 p21(Cip1) 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.

Activity of the Selective IκB kinase Inhibitor BMS-345541 against T-Cell Acute Lymphoblastic Leukemia: involvement of FOXO3a

BUONTEMPO, FRANCESCA;BRESSANIN, DANIELA;PESSION, ANDREA;MARTELLI, ALBERTO MARIA
2012

Abstract

Several lines of evidence suggest that the I kappa B kinase (IKK)/nuclear factor kappa B (NF kappa B) 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 NF kappa B 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 G(2)/M phase of the cell cycle via inhibition of IKK/NF kappa B 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 p21(Cip1) 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.
F. Buontempo; F. Chiarini; D. Bressanin; G. Tabellini; F. Melchionda; A. Pession; M. Fini; L.M. Neri; J.A. McCubrey; A.M. Martelli
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/117914
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