Proteasome inhibitors induce apoptosis in glucocorticoid-resistant chronic lymphocytic leukemic lymphocytes

Our previous work showed that the nuclear scaffold (NS) protease is required for apoptosis of both thymocytes and chronic lymphocytic leukemic (CLL) lymphocytes. Because partial sequencing of one of the subunits of the NS protease revealed homology to the proteasome, we tested the effects of classic...

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Bibliographic Details
Published in:Blood 1998-12, Vol.92 (11), p.4220-4229
Main Authors: CHANDRA, J, NIEMER, I, GILBREATH, J, KLICHE, K.-O, ANDREEFF, M, FREIREICH, E. J, KEATING, M, MCCONKEY, D. J
Format: Article
Language:English
Subjects:
Antineoplastic agents
Apoptosis - drug effects
Biological and medical sciences
Cysteine Endopeptidases - drug effects
Cysteine Proteinase Inhibitors - pharmacology
Drug Resistance, Neoplasm
General aspects
Glucocorticoids - pharmacology
Glucocorticoids - therapeutic use
Humans
Intracellular Membranes - drug effects
Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy
Leukemia, Lymphocytic, Chronic, B-Cell - pathology
Lymphocyte Activation - drug effects
Lymphocytes - pathology
Medical sciences
Multienzyme Complexes - drug effects
Pharmacology. Drug treatments
Proteasome Endopeptidase Complex
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Summary:Our previous work showed that the nuclear scaffold (NS) protease is required for apoptosis of both thymocytes and chronic lymphocytic leukemic (CLL) lymphocytes. Because partial sequencing of one of the subunits of the NS protease revealed homology to the proteasome, we tested the effects of classical proteasome inhibitors on apoptosis in CLL cells. Here we report that proteasome inhibition caused high levels of DNA fragmentation in all patients analyzed, including those resistant to glucocorticoids or nucleoside analogs, in vitro. Proteasome inhibitor-induced DNA fragmentation was associated with activation of caspase/ICE family cysteine protease(s) and was blocked by the caspase antagonist, zVADfmk. Analysis of the biochemical mechanisms involved showed that proteasome inhibition resulted in mitochondrial dysregulation leading to the release of cytochrome c and a drop in mitochondrial transmembrane potential (triangle upPsi). These changes were associated with inhibition of NFkappaB, a proteasome-regulated transcription factor that has been implicated in the suppression of apoptosis in other systems. Together, our results suggest that drugs that target the proteasome might be capable of bypassing resistance to conventional chemotherapy in CLL.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.v92.11.4220