SEARCH:   Advanced

Blood, 15 July 2004, Vol. 104, No. 2, pp. 509-518. Prepublished online as a Blood First Edition Paper on March 23, 2004; DOI 10.1182/blood-2003-12-4121. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-12-4121v1 104/2/509    most recent 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 Dai, Y. Articles by Grant, S. Search for Related Content PubMed PubMed Citation Articles by Dai, Y. Articles by Grant, S. Related Collections Neoplasia Apoptosis Cell Cycle Oncogenes and Tumor Suppressors Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms Yun Dai, Mohamed Rahmani, Xin-Yan Pei, Paul Dent, and Steven Grant From the Departments of Medicine, Radiation Oncology, Biochemistry, and Pharmacology, Virginia Commonwealth University, Medical College of Virginia, Richmond, VA. Interactions between the cyclin-dependent kinase (CDK) inhibitor flavopiridol and the proteasome inhibitor bortezomib were examined in Bcr/Abl+ human leukemia cells. Coexposure of K562 or LAMA84 cells to subtoxic concentration of flavopiridol (150-200 nM) and bortezomib (5-8 nM) resulted in a synergistic increase in mitochondrial dysfunction and apoptosis. These events were associated with a marked diminution in nuclear factor B (NF-B)/DNA binding activity; enhanced phosphorylation of SEK1/MKK4 (stress-activated protein kinase/extracellular signal-related kinase 1/mitogen-activated protein kinase kinase 4), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK); down-regulation of Bcr/Abl; and a marked reduction in signal transducer and activator of transcription 3 (STAT3) and STAT5 activity. In imatinib mesylate-resistant K562 cells displaying increased Bcr/Abl expression, bortezomib/flavopiridol treatment markedly increased apoptosis in association with down-regulation of Bcr/Abl and BclxL, and diminished phosphorylation of Lyn, Hck, CrkL, and Akt. Parallel studies were performed in imatinib mesylate-resistant LAMA84 cells exhibiting reduced expression of Bcr/Abl but a marked increase in expression/activation of Lyn and Hck. Flavopiridol/bortezomib effectively induced apoptosis in these cells in association with Lyn and Hck inactivation. The capacity of flavopiridol to promote bortezomib-mediated Bcr/Abl down-regulation and apoptosis was mimicked by the positive transcription elongation factor-b (P-TEFb) inhibitor DRB (5,6-dichloro 1--D-ribofuranosylbenzinida-sole). Finally, the bortezomib/flavopiridol regimen also potently induced apoptosis in Bcr/Abl- human leukemia cells. Collectively, these findings suggest that a strategy combining flavopiridol and bortezomib warrants further examination in chronic myelogenous leukemia and related hematologic malignancies. (Blood. 2004;104:509-518) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: 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] A. Ferrajoli, S. Faderl, Q. Van, P. Koch, D. Harris, Z. Liu, I. Hazan-Halevy, Y. Wang, H. M. Kantarjian, W. Priebe, et al. WP1066 Disrupts Janus Kinase-2 and Induces Caspase-Dependent Apoptosis in Acute Myelogenous Leukemia Cells Cancer Res., December 1, 2007; 67(23): 11291 - 11299. [Abstract] [Full Text] [PDF] D. Cilloni, G. Martinelli, F. Messa, M. Baccarani, and G. Saglio Nuclear factor {kappa}B as a target for new drug development in myeloid malignancies Haematologica, September 1, 2007; 92(9): 1224 - 1229. [Abstract] [Full Text] [PDF] G. A. Bartholomeusz, M. Talpaz, V. Kapuria, L. Y. Kong, S. Wang, Z. Estrov, W. Priebe, J. Wu, and N. J. Donato Activation of a novel Bcr/Abl destruction pathway by WP1130 induces apoptosis of chronic myelogenous leukemia cells Blood, April 15, 2007; 109(8): 3470 - 3478. [Abstract] [Full Text] [PDF] W. Fiskus, M. Pranpat, M. Balasis, P. Bali, V. Estrella, S. Kumaraswamy, R. Rao, K. Rocha, B. Herger, F. Lee, et al. Cotreatment with Vorinostat (Suberoylanilide Hydroxamic Acid) Enhances Activity of Dasatinib (BMS-354825) against Imatinib Mesylate-Sensitive or Imatinib Mesylate-Resistant Chronic Myelogenous Leukemia Cells. Clin. Cancer Res., October 1, 2006; 12(19): 5869 - 5878. [Abstract] [Full Text] [PDF] M. Baccarani, G. Saglio, J. Goldman, A. Hochhaus, B. Simonsson, F. Appelbaum, J. Apperley, F. Cervantes, J. Cortes, M. Deininger, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet Blood, September 15, 2006; 108(6): 1809 - 1820. [Abstract] [Full Text] [PDF] C. Yu, B. B. Friday, J.-P. Lai, L. Yang, J. Sarkaria, N. E. Kay, C. A. Carter, L. R. Roberts, S. H. Kaufmann, and A. A. Adjei Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways. Mol. Cancer Ther., September 1, 2006; 5(9): 2378 - 2387. [Abstract] [Full Text] [PDF] W. Fiskus, M. Pranpat, P. Bali, M. Balasis, S. Kumaraswamy, S. Boyapalle, K. Rocha, J. Wu, F. Giles, P. W. Manley, et al. Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl-expressing human leukemia cells Blood, July 15, 2006; 108(2): 645 - 652. [Abstract] [Full Text] [PDF] E. B. Sambol, G. Ambrosini, R. C. Geha, P. T. Kennealey, P. DeCarolis, R. O'Connor, Y. V. Wu, M. Motwani, J.-H. Chen, G. K. Schwartz, et al. Flavopiridol Targets c-KIT Transcription and Induces Apoptosis in Gastrointestinal Stromal Tumor Cells Cancer Res., June 1, 2006; 66(11): 5858 - 5866. [Abstract] [Full Text] [PDF] T. Khan, J. K. Stauffer, R. Williams, J. A. Hixon, R. Salcedo, E. Lincoln, T. C. Back, D. Powell, S. Lockett, A. C. Arnold, et al. Proteasome Inhibition to Maximize the Apoptotic Potential of Cytokine Therapy for Murine Neuroblastoma Tumors J. Immunol., May 15, 2006; 176(10): 6302 - 6312. [Abstract] [Full Text] [PDF] S. Grant, D. Sullivan, D. Roodman, R. Stuart, E. B. Perkins, V. Ramakrishnan, J. Wright, A. D. Colevas, and J. D. Roberts Phase I Trial of Bortezomib (NSC 681239) and Flavopiridol (NSC 649890) in Patients with Recurrent or Refractory Indolent B-Cell Neoplasms. Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 3338 - 3338. [Abstract] W. S. El-Deiry Meeting Report: The International Conference on Tumor Progression and Therapeutic Resistance Cancer Res., June 1, 2005; 65(11): 4475 - 4484. [Abstract] [Full Text] [PDF] P.-H. Tseng, H.-P. Lin, J. Zhu, K.-F. Chen, E. M. Hade, D. C. Young, J. C. Byrd, M. Grever, K. Johnson, B. J. Druker, et al. Synergistic interactions between imatinib mesylate and the novel phosphoinositide-dependent kinase-1 inhibitor OSU-03012 in overcoming imatinib mesylate resistance Blood, May 15, 2005; 105(10): 4021 - 4027. [Abstract] [Full Text] [PDF]

	Copyright © 2004 by American Society of Hematology         Online ISSN: 1528-0020