p65 Activity and ZAP-70 Status Predict the Sensitivity of Chronic Lymphocytic Leukemia Cells to the Selective IκB Kinase Inhibitor BMS-345541
Purpose: Constitutive nuclear factor-κB (NF-κB) activation has been implicated in the pathogenesis of chronic lymphocytic leukemia (CLL). Our purpose was to characterize the molecular mechanisms underlying for the selective IκB kinase inhibitor BMS-345541 in CLL cells together with the analysis of i...
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Published in | Clinical cancer research Vol. 15; no. 8; pp. 2767 - 2776 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Philadelphia, PA
American Association for Cancer Research
15.04.2009
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Subjects | |
Online Access | Get full text |
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Summary: | Purpose: Constitutive nuclear factor-κB (NF-κB) activation has been implicated in the pathogenesis of chronic lymphocytic leukemia
(CLL). Our purpose was to characterize the molecular mechanisms underlying for the selective IκB kinase inhibitor BMS-345541
in CLL cells together with the analysis of its combination with several antineoplasic drugs.
Experimental Design: Primary cells from 34 CLL patients were incubated with different doses of BMS-345541. NF-κB DNA-binding activity was analyzed
by ELISA-based kits and the characterization of the apoptotic pathway was done by flow cytometry, immunoblotting, quantitative
reverse transcription-PCR, and immunofluorescence techniques.
Results: BMS-345541 selectively induced apoptosis in CLL cells in the low micromolar range irrespective of p53 status. Noteworthy,
the high ZAP-70 group was significantly more sensitive to BMS-345541 than the low ZAP-70 group, in correlation with high levels
of p65 phosphorylation and DNA-binding activity. Following NF-κB inhibition, BMS-345541 led to induction of the mitochondrial
apoptotic pathway and activation of both caspase-dependent and caspase-independent factors. Moreover, BMS-345541-induced apoptosis
was accompanied by down-regulation of several antiapoptotic NF-κB-target genes, including both BCL2 family members and apoptotic
endogenous inhibitors. In addition, we showed a strong synergism between BMS-345541 and conventional chemotherapeutics such
as mitoxantrone and dexamethasone as well as with new promising drugs such as the BH3-mimetic GX15-070/Obatoclax or the anti-TRAIL-R1
monoclonal antibody mapatumumab.
Conclusions: These data confirm that NF-κB is a relevant target in CLL and indicate that inhibitors of IκB kinase, alone or in combination,
represent a novel therapeutic strategy for the treatment of CLL patients, especially for the group with high ZAP-70. |
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ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-08-2382 |