marizomib has been researched along with Leukemia--Lymphocytic--Chronic--B-Cell* in 2 studies
2 other study(ies) available for marizomib and Leukemia--Lymphocytic--Chronic--B-Cell
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Caspase-8 dependent histone acetylation by a novel proteasome inhibitor, NPI-0052: a mechanism for synergy in leukemia cells.
Combination studies of histone deacetylase inhibitors (HDACi) and proteasome inhibitors are providing preclinical framework to build better strategies against hematologic malignancies. Our previous work found that a novel proteasome inhibitor, NPI-0052, and HDACi synergistically induce apoptosis in leukemia cells in a caspase-8- and oxidant-dependent manner. Here we extend those observations to primary leukemia cells and identify novel mechanisms of synergy. Because the proximal targets of NPI-0052 and HDACi are inhibition of proteasome activity and histone acetylation, we initially examined those biochemical events. Increased acetylation of histone-H3 was detected in Jurkat and CLL primary cells treated with NPI-0052, alone or in combination with various HDACi (MS/SNDX-275 or vorinostat). Hyperacetylation by NPI-0052 occurred to a lesser extent in caspase-8-deficient cells and in cells treated with an antioxidant. These results indicate that NPI-0052 is eliciting caspase-8 and oxidative stress-dependent epigenetic alterations. In addition, real-time PCR revealed that MS/SNDX-275 repressed expression of the proteasomal beta5, beta2, and beta1 subunits, consequently inhibiting respective enzymatic activities. Overall, our results suggest that crosstalk by NPI-0052 and HDACi are contributing, along with caspase-8 activation and oxidative stress, to their synergistic cytotoxic effects in leukemia cells, reinforcing the potential clinical utility of combining these 2 agents. Topics: Acetylation; Antioxidants; Apoptosis; Boronic Acids; Bortezomib; Caspase 8; Drug Synergism; Drug Therapy, Combination; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Immunoblotting; Immunoprecipitation; Lactones; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Oxidative Stress; Protease Inhibitors; Proteasome Inhibitors; Protein Processing, Post-Translational; Pyrazines; Pyrroles; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Superoxides; Tumor Cells, Cultured; Vorinostat | 2009 |
The proteasome inhibitor NPI-0052 is a more effective inducer of apoptosis than bortezomib in lymphocytes from patients with chronic lymphocytic leukemia.
Proteasome inhibitors are potent inducers of apoptosis in isolated lymphocytes from patients with chronic lymphocytic leukemia (CLL). However, the reversible proteasome inhibitor bortezomib (PS-341; Velcade) did not display substantial antitumor activity in CLL patients. Here, we compared the effects of bortezomib and a new irreversible proteasome inhibitor (NPI-0052) on 20S chymotryptic proteasome activity and apoptosis in isolated CLL cells in vitro. Although their steady-state (3 hours) IC(50)s as proteasome inhibitors were similar, NPI-0052 exerted its effects more rapidly than bortezomib, and drug washout experiments showed that short exposures to NPI-0052 resulted in sustained (> or =24 hours) 20S proteasome inhibition, whereas 20S activity recovered in cells exposed to even 10-fold higher concentrations of bortezomib. Thus, brief (15 minutes) pulses of NPI-0052 were sufficient to induce substantial apoptosis in CLL cells, whereas longer exposure times (> or =8 hours) were required for commitment to apoptosis in cells exposed to equivalent concentrations of bortezomib. Commitment to apoptosis seemed to be related to caspase-4 activation, in that cells exposed to bortezomib or NPI-0052 could be saved from death by addition of a selective caspase-4 inhibitor up to 8 hours after drug exposure. Our results show that NPI-0052 is a more effective proapoptotic agent than bortezomib in isolated CLL cells and suggest that the chemical properties of NPI-0052 might also make it an effective therapeutic agent in CLL patients. Topics: Antineoplastic Agents; Apoptosis; Boronic Acids; Bortezomib; Humans; Lactones; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytes; Protease Inhibitors; Proteasome Inhibitors; Pyrazines; Pyrroles | 2006 |