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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2501-2506. Prepublished online as a Blood First Edition Paper on November 15, 2005; DOI 10.1182/blood-2005-07-2966. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-07-2966v1 107/6/2501    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 Chandra, J. Articles by Kaufmann, S. H. Search for Related Content PubMed PubMed Citation Articles by Chandra, J. Articles by Kaufmann, S. H. Related Collections Neoplasia Oncogenes and Tumor Suppressors Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Adaphostin-induced oxidative stress overcomes BCR/ABL mutation-dependent and -independent imatinib resistance Joya Chandra, Jeannette Tracy, David Loegering, Karen Flatten, Srdan Verstovsek, Miloslav Beran, Mercedes Gorre, Zeev Estrov, Nicholas Donato, Moshe Talpaz, Charles Sawyers, Kapil Bhalla, Judith Karp, Edward Sausville, and Scott H. Kaufmann From the Departments of Pediatrics Research, Experimental Therapeutics and Leukemia, M.D. Anderson Cancer Center, Houston, TX; the Divisions of Oncology Research and Hematology, Mayo Clinic, Rochester, MN; the Department of Hematology-Oncology, UCLA, Los Angeles, CA; the Interdisciplinary Oncology Program, H. Lee Moffitt Cancer Center, Tampa, FL; the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; and the University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD. The BCR/ABL kinase has been targeted for the treatment of chronic myelogenous leukemia (CML) by imatinib mesylate. While imatinib has been extremely effective for chronic phase CML, blast crisis CML and Ph+ acute lymphoblastic leukemia (ALL) are often resistant. In particular, mutation of the T315 residue in the bcr/abl activation loop renders cells highly resistant to imatinib and to secondgeneration kinase inhibitors such as BMS-354825 or AMN107. Adaphostin is a tyrphostin that was originally intended to inhibit the BCR/ABL kinase by competing with its peptide substrates. Recent findings have in addition implicated reactive oxygen species (ROS) in the cytotoxic mechanism of adaphostin. In view of this unique mode of action, we examined the effects of adaphostin on numerous imatinib-resistant leukemia models, including imatinib-resistant CML and Ph+ ALL cell lines, cells harboring point mutations in BCR/ABL, and specimens from imatinib-resistant CML patients, using assays for intracellular ROS, apoptosis, and clonogenicity. Every model of imatinib resistance examined remained fully sensitive to adaphostin-induced cell death. Collectively, these data suggest that ROS generation by adaphostin overcomes even the most potent imatinib resistance in CML and Ph+ ALL. (Blood. 2006;107: 2501-2506) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: ROS: double-edged sword for leukemic cells Neil E. Kay Blood 2006 107: 2212-2213. [Full Text] [PDF] This article has been cited by other articles: J. Zhang, M. Sattler, G. Tonon, C. Grabher, S. Lababidi, A. Zimmerhackl, M. S. Raab, S. Vallet, Y. Zhou, M.-A. Cartron, et al. Targeting Angiogenesis via a c-Myc/Hypoxia-Inducible Factor-1{alpha}-Dependent Pathway in Multiple Myeloma Cancer Res., June 15, 2009; 69(12): 5082 - 5090. [Abstract] [Full Text] [PDF] S. Bhalla, S. Balasubramanian, K. David, M. Sirisawad, J. Buggy, L. Mauro, S. Prachand, R. Miller, L. I. Gordon, and A. M. Evens PCI-24781 Induces Caspase and Reactive Oxygen Species-Dependent Apoptosis Through NF-{kappa}B Mechanisms and Is Synergistic with Bortezomib in Lymphoma Cells Clin. Cancer Res., May 15, 2009; 15(10): 3354 - 3365. [Abstract] [Full Text] [PDF] X. Shi, Y. Jin, C. Cheng, H. Zhang, W. Zou, Q. Zheng, Z. Lu, Q. Chen, Y. Lai, and J. Pan Triptolide Inhibits Bcr-Abl Transcription and Induces Apoptosis in STI571-resistant Chronic Myelogenous Leukemia Cells Harboring T315I Mutation Clin. Cancer Res., March 1, 2009; 15(5): 1686 - 1697. [Abstract] [Full Text] [PDF] S. Monteghirfo, F. Tosetti, C. Ambrosini, S. Stigliani, S. Pozzi, F. Frassoni, G. Fassina, S. Soverini, A. 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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] L. H. Stockwin, M. A. Bumke, S. X. Yu, S. P. Webb, J. R. Collins, M. G. Hollingshead, and D. L. Newton Proteomic Analysis Identifies Oxidative Stress Induction by Adaphostin Clin. Cancer Res., June 15, 2007; 13(12): 3667 - 3681. [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] S. B. Le, M. K. Hailer, S. Buhrow, Q. Wang, K. Flatten, P. Pediaditakis, K. C. Bible, L. D. Lewis, E. A. Sausville, Y.-P. Pang, et al. 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