Proteasome inhibition in myelodysplastic syndromes and acute myelogenous leukemia cell lines.
ABSTRACT In this work, effects of bortezomib on apoptosis, clonal progenitor growth, cytokine production, and NF-κB expression in patients with MDS with cytopenias requiring transfusion support are examined. Bortezomib increased apoptosis in marrow mononuclear cells but had no effects on CFU-GM, BFU-E, or CFU-L content. No consistent effects on NF-κB activation in vivo were noted. To further define the role of bortezomib in AML and MDS, we examined it in combination with several targeted agents and chemotherapeutic agents in vitro. Combinations with arsenic trioxide, sorafenib, and cytarabine demonstrated synergistic in vitro effects in AML cell lines.
SourceAvailable from: Sudipto Mukherjee[Show abstract] [Hide abstract]
ABSTRACT: The myelodysplastic syndromes (MDS) are a heterogenous collection of clonal hematopoietic malignancies that exist as a subgroup of the myeloid neoplasms as classified by the World Health Organization (WHO). They are characterized by ineffective hematopoiesis, subsequent cytopenias, transformation to acute myeloid leukemia (AML), and poor overall survival. There are currently three FDA-approved medications for MDS; lenalidomide, azacitidine, and decitabine. The role of these agents is to diminish the clinical impact of MDS and delay its progression to AML. However, despite known results with these monotherapies, recent clinical trials with a variety of combinations for MDS have demonstrated promising results. These trials include combinations of hypomethylating agents, histone deacetylase inhibitors, growth factors, and chemotherapy among others. In this paper we review the current literature on combination therapies in MDS, analyze on-going and concluded trials, and suggest future possibilities for combination strategies in MDS. Copyright © 2014 Elsevier Ltd. All rights reserved.Bailliè re s Best Practice and Research in Clinical Haematology 11/2014; 28(1). DOI:10.1016/j.beha.2014.11.002 · 2.55 Impact Factor
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ABSTRACT: We conducted a phase I dose escalation study to determine the maximal tolerated dose of bortezomib that could be combined with standard dose lenalidomide in patients with MDS or AML. Treatment consisted of bortezomib (IV) on Days 1, 4, 8, and 11 and lenalidomide 10mg daily (PO) days 1-21 in 28 day cycles for up to 9 cycles. 23 patients (14 MDS/CMML, 9 AML) were enrolled. The maximally tested dose of bortezomib, 1.3mg/m(2), was tolerable in this regimen. Responses were seen in patients with MDS and AML. Further testing of this regimen is planned.Leukemia research 06/2013; DOI:10.1016/j.leukres.2013.05.011 · 2.69 Impact Factor
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ABSTRACT: Sustained NF-ĸB activation is often observed in Acute Myeloid Leukemia (AML) and proteasome inhibition has therefore been proposed to efficiently target AML cells. In the present study, we questioned whether leukemic stem cell enriched CD34(+) cells are sensitive to the proteasome inhibitor bortezomib. Surprisingly, we observed in short-term and long-term culture assays that CD34(-) AML cells were more sensitive to bortezomib treatment compared to the CD34(+) AML cells at a clinical relevant dosage. Co-treatment with the apoptosis inducing cytokine TRAIL did not further enhance cell death in CD34(+) AML cells in contrast to the effects in AML cell lines. The better survival of CD34(+) AML cells upon bortezomib treatment was due to a persisting NF-ĸB activity which could be overcome by the IKK inhibitor BMS-345541. This difference in sensitivity might be related to differences in NF-ĸB activation in AML CD34(+) versus CD34(-) cells as suggested by a gene expression profiling study. Besides NF-ĸB, MCL-1 strongly determines the effectiveness of bortezomib. MCL-1 accumulated in CD34(+) AML cells upon bortezomib treatment and inhibition of MCL-1 by shRNA or obatoclax, significantly improved the sensitivity of CD34(+) AML cells to bortezomib. These results demonstrate that combining bortezomib with specific NF-ĸB or MCL-1 inhibitors might potentially target the leukemic stem cells.Experimental hematology 02/2013; 41(6). DOI:10.1016/j.exphem.2013.02.002 · 2.81 Impact Factor