PURPOSE: Constitutive nuclear factor-kappaB (NF-kappaB) activation has been implicated in the pathogenesis of chronic lymphocytic leukemia (CLL). Our purpose was to characterize the molecular mechanisms underlying for the selective IkappaB 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-kappaB 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-kappaB 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-kappaB-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-kappaB is a relevant target in CLL and indicate that inhibitors of IkappaB kinase, alone or in combination, represent a novel therapeutic strategy for the treatment of CLL patients, especially for the group with high ZAP-70.
PURPOSE: Constitutive nuclear factor-kappaB (NF-kappaB) activation has been implicated in the pathogenesis of chronic lymphocytic leukemia (CLL). Our purpose was to characterize the molecular mechanisms underlying for the selective IkappaB kinase inhibitor BMS-345541 in CLL cells together with the analysis of its combination with several antineoplasic drugs. EXPERIMENTAL DESIGN: Primary cells from 34 CLLpatients were incubated with different doses of BMS-345541. NF-kappaB 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-kappaB 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-kappaB-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-kappaB is a relevant target in CLL and indicate that inhibitors of IkappaB kinase, alone or in combination, represent a novel therapeutic strategy for the treatment of CLLpatients, especially for the group with high ZAP-70.
Authors: D Benedetti; E Tissino; F Pozzo; T Bittolo; C Caldana; C Perini; D Martorelli; V Bravin; T D'Agaro; F M Rossi; R Bomben; E Santinelli; F Zaja; G Pozzato; A Chiarenza; F Di Raimondo; G Del Poeta; D Rossi; G Gaidano; M Dal Bo; V Gattei; A Zucchetto Journal: Leukemia Date: 2017-09-22 Impact factor: 11.528
Authors: Timothy L Chen; Minh Tran; Aparna Lakshmanan; Bonnie K Harrington; Nikhil Gupta; Virginia M Goettl; Amy M Lehman; Stephen Trudeau; David M Lucas; Amy J Johnson; John C Byrd; Erin Hertlein Journal: Blood Date: 2017-05-17 Impact factor: 22.113
Authors: Nagendra K Chaturvedi; Rajkumar N Rajule; Ashima Shukla; Prakash Radhakrishnan; Gordon L Todd; Amarnath Natarajan; Julie M Vose; Shantaram S Joshi Journal: Mol Cancer Ther Date: 2013-08-20 Impact factor: 6.261
Authors: R F Dielschneider; W Xiao; J-Y Yoon; E Noh; V Banerji; H Li; A J Marshall; J B Johnston; S B Gibson Journal: Cell Death Dis Date: 2014-10-02 Impact factor: 8.469