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

被引:39
作者
Buontempo, Francesca [2 ]
Chiarini, Francesca [1 ]
Bressanin, Daniela [3 ]
Tabellini, Giovanna [4 ]
Melchionda, Fraia [5 ]
Pession, Andrea [5 ]
Fini, Milena [2 ]
Neri, Luca M. [6 ]
McCubrey, James A. [7 ]
Martelli, Alberto M. [1 ,3 ]
机构
[1] CNR, Rizzoli Orthoped Inst, Inst Mol Genet, Bologna, Italy
[2] Rizzoli Orthoped Inst, Lab Preclin & Surg Studies, Bologna, Italy
[3] Univ Bologna, Dept Human Anat, Bologna, Italy
[4] Univ Brescia, Dept Biomed Sci & Biotechnol, Brescia, Italy
[5] Univ Bologna, Paediat Oncol & Hematol Unit Lalla Seragnoli, Bologna, Italy
[6] Univ Ferrara, Dept Morphol & Embryol, I-44100 Ferrara, Italy
[7] E Carolina Univ, Brody Sch Med, Dept Microbiol & Immunol, Greenville, NC USA
关键词
T-cell acute lymphoblastic leukemia; BMS-345541; IKK; NF kappa B; FOXO3a; cell cycle; apoptosis; FORKHEAD TRANSCRIPTION FACTOR; ACUTE MYELOID-LEUKEMIA; PROMOTES TUMORIGENESIS; SIGNALING PATHWAY; FACTOR FKHR-L1; CANCER; NOTCH; EXPRESSION; P27(KIP1); PHOSPHORYLATION;
D O I
10.4161/cc.20859
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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. 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.
引用
收藏
页码:2467 / 2475
页数:9
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