DOI: 10.1182/blood.v92.11.4220. Proteasome Inhibitors Induce Apoptosis in Glucocorticoid-Resistant Chronic Lymphocytic Leukemic Lymphocytes

Proteasome Inhibitors Induce Apoptosis in Glucocorticoid-Resistant Chronic Lymphocytic Leukemic Lymphocytes

10.1182/blood.v92.11.4220

Crossref journal-article

American Society of Hematology

Blood (234)

Abstract

AbstractOur 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 (▵Ψ). These changes were associated with inhibition of NFκB, 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.

Bibliography

Chandra, J., Niemer, I., Gilbreath, J., Kliche, K.-O., Andreeff, M., Freireich, E. J., Keating, M., & McConkey, D. J. (1998). Proteasome Inhibitors Induce Apoptosis in Glucocorticoid-Resistant Chronic Lymphocytic Leukemic Lymphocytes. Blood, 92(11), 4220â4229.

Authors 8

Joya Chandra (first)
Irina Niemer (additional)
Joyce Gilbreath (additional)
Kay-Oliver Kliche (additional)
Michael Andreeff (additional)
Emil J. Freireich (additional)
Michael Keating (additional)
David J. McConkey (additional)

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Dates

Type	When
Created	5 years, 10 months ago (Oct. 14, 2019, 7:55 a.m.)
Deposited	1 year, 11 months ago (Sept. 21, 2023, 12:54 p.m.)
Indexed	3 weeks, 6 days ago (July 30, 2025, 10:27 a.m.)
Issued	26 years, 8 months ago (Dec. 1, 1998)
Published	26 years, 8 months ago (Dec. 1, 1998)
Published Print	26 years, 8 months ago (Dec. 1, 1998)

Funders 0

None

BibTeX

@article{Chandra_1998, title={Proteasome Inhibitors Induce Apoptosis in Glucocorticoid-Resistant Chronic Lymphocytic Leukemic Lymphocytes}, volume={92}, ISSN={0006-4971}, url={http://dx.doi.org/10.1182/blood.v92.11.4220}, DOI={10.1182/blood.v92.11.4220}, number={11}, journal={Blood}, publisher={American Society of Hematology}, author={Chandra, Joya and Niemer, Irina and Gilbreath, Joyce and Kliche, Kay-Oliver and Andreeff, Michael and Freireich, Emil J. and Keating, Michael and McConkey, David J.}, year={1998}, month=dec, pages={4220–4229} }

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