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This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chandra, J. Articles by McConkey, D. J. Search for Related Content PubMed PubMed Citation Articles by Chandra, J. Articles by McConkey, D. J. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, Vol. 92 No. 11 (December 1), 1998: pp. 4220-4229 Proteasome Inhibitors Induce Apoptosis in Glucocorticoid-Resistant Chronic Lymphocytic Leukemic Lymphocytes Joya Chandra, Irina Niemer, Joyce Gilbreath, Kay-Oliver Kliche, Michael Andreeff, Emil J. Freireich, Michael Keating, and David J. McConkey From the Departments of Cell Biology and Hematology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX. 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 (). These changes were associated with inhibition of NFB, 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. Gao, A. Howard, K. Ban, and J. Chandra Oxidative Stress Promotes Transcriptional Up-regulation of Fyn in BCR-ABL1-expressing Cells J. Biol. Chem., March 13, 2009; 284(11): 7114 - 7125. [Abstract] [Full Text] [PDF] L. Tonnetti, S. Netzel-Arnett, G. A. Darnell, T. Hayes, M. S. Buzza, I. E. Anglin, A. Suhrbier, and T. M. Antalis SerpinB2 Protection of Retinoblastoma Protein from Calpain Enhances Tumor Cell Survival Cancer Res., July 15, 2008; 68(14): 5648 - 5657. [Abstract] [Full Text] [PDF] Y. Dai, S. Chen, L. B. Kramer, V. L. Funk, P. Dent, and S. Grant Interactions between Bortezomib and Romidepsin and Belinostat in Chronic Lymphocytic Leukemia Cells Clin. Cancer Res., January 15, 2008; 14(2): 549 - 558. [Abstract] [Full Text] [PDF] F. Zaman, V. Menendez-Benito, E. Eriksson, A. S. Chagin, M. Takigawa, B. Fadeel, N. P. Dantuma, D. Chrysis, and L. Savendahl Proteasome Inhibition Up-regulates p53 and Apoptosis-Inducing Factor in Chondrocytes Causing Severe Growth Retardation in Mice Cancer Res., October 15, 2007; 67(20): 10078 - 10086. [Abstract] [Full Text] [PDF] C. P. Miller, K. Ban, M. E. Dujka, D. J. McConkey, M. Munsell, M. Palladino, and J. Chandra NPI-0052, a novel proteasome inhibitor, induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells Blood, July 1, 2007; 110(1): 267 - 277. [Abstract] [Full Text] [PDF] S. Ruiz, Y. Krupnik, M. Keating, J. Chandra, M. Palladino, and D. McConkey The proteasome inhibitor NPI-0052 is a more effective inducer of apoptosis than bortezomib in lymphocytes from patients with chronic lymphocytic leukemia. Mol. Cancer Ther., July 1, 2006; 5(7): 1836 - 1843. [Abstract] [Full Text] [PDF] J. Chandra, J. Tracy, D. Loegering, K. Flatten, S. Verstovsek, M. Beran, M. Gorre, Z. Estrov, N. Donato, M. Talpaz, et al. Adaphostin-induced oxidative stress overcomes BCR/ABL mutation-dependent and -independent imatinib resistance Blood, March 15, 2006; 107(6): 2501 - 2506. [Abstract] [Full Text] [PDF] S. Mitra-Kaushik, J. C. Harding, J. L. Hess, and L. Ratner Effects of the proteasome inhibitor PS-341 on tumor growth in HTLV-1 Tax transgenic mice and Tax tumor transplants Blood, August 1, 2004; 104(3): 802 - 809. [Abstract] [Full Text] [PDF] J. Cortes, D. Thomas, C. Koller, F. Giles, E. Estey, S. Faderl, G. Garcia-Manero, D. McConkey, G. Patel, R. Guerciolini, et al. Phase I Study of Bortezomib in Refractory or Relapsed Acute Leukemias Clin. Cancer Res., May 15, 2004; 10(10): 3371 - 3376. [Abstract] [Full Text] [PDF] A. M. Kamat, T. Karashima, D. W. Davis, L. Lashinger, M. Bar-Eli, R. Millikan, Y. Shen, C. P. N. Dinney, and D. J. McConkey The proteasome inhibitor bortezomib synergizes with gemcitabine to block the growth of human 253JB-V bladder tumors in vivo Mol. Cancer Ther., March 1, 2004; 3(3): 279 - 290. [Abstract] [Full Text] D. T. Jones, E. Addison, J. M. North, M. W. Lowdell, A. V. Hoffbrand, A. B. Mehta, K. Ganeshaguru, N. I. Folarin, and R. G. 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Lopez-Rivas Interferon-gamma Sensitizes Human Myeloid Leukemia Cells to Death Receptor-mediated Apoptosis by a Pleiotropic Mechanism J. Biol. Chem., May 18, 2001; 276(21): 17779 - 17787. [Abstract] [Full Text] [PDF]

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