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Prepublished online as a Blood First Edition Paper on August 14, 2003; DOI 10.1182/blood-2003-02-0562. This Article Full Text (PDF) All Versions of this Article: 2003-02-0562v1 102/13/4512    most recent Alert me when this article is cited Alert me if a correction is posted 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 Social Bookmarking                   What's this? Submitted February 20, 2003 Accepted July 25, 2003 Involvement of reactive oxygen species in adaphostin-induced cytotoxicity in human leukemia cells Joya Chandra, Jennifer Hackbarth, Son Le, David Loegering, Nancy Bone, Laura M Bruzek, Ven L Narayanan, Alex A Adjei, Neil E Kay, Ayalew Tefferi, Judith E Karp, Edward A Sausville, and Scott H Kaufmann* Department of Oncology, Mayo Clinic, Rochester, MN, USA; Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA Department of Biochemistry & Molecular Biology, Mayo Graduate School, Rochester, MN, USA Developmental Therapeutics Program, National Cancer Institute, Bethesda, MD, USA Greenbaum Cancer Center, University of Maryland, Baltimore, MD, USA * Corresponding author; email: Kaufmann.Scott{at}Mayo.edu. Adaphostin (NSC 680410), an analogue of the tyrphostin AG957, was previously shown to induce Bcr/abl downregulation followed by loss of clonogenic survival in chronic myelogenous leukemia (CML) cell lines and clinical samples. Adaphostin demonstrated selectivity for CML myeloid progenitors in vitro and remained active in K562 cells selected for imatinib mesylate resistance. In the present study, the mechanism of action of adaphostin was investigated in greater detail in vitro. Initial studies demonstrated that adaphostin induced apoptosis in a variety of Bcr/abl-negative cells, including acute myelogenous leukemia (AML) blasts and cell lines as well as chronic lymphocytic leukemia (CLL) samples. Further study demonstrated that adaphostin caused intracellular peroxide production followed by DNA strand breaks and, in cells containing wildtype p53, a typical DNA damage response consisting of p53 phosphorylation and upregulation. Importantly, the antioxidant N-acetylcysteine (NAC) blunted these events, whereas glutathione depletion with buthionine sulfoximine (BSO) augmented them. Collectively, these results not only outline a mechanism by which adaphostin can damage both myeloid and lymphoid leukemia cells, but also indicate that this novel agent might have a broader spectrum of activity than originally envisioned. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. Ban, Y. Gao, H. M. Amin, A. Howard, C. Miller, Q. Lin, X. Leng, M. Munsell, M. Bar-Eli, R. B. Arlinghaus, et al. BCR-ABL1 mediates up-regulation of Fyn in chronic myelogenous leukemia Blood, March 1, 2008; 111(5): 2904 - 2908. [Abstract] [Full Text] [PDF] X. W. Meng, S.-H. Lee, H. Dai, D. Loegering, C. Yu, K. Flatten, P. Schneider, N. T. Dai, S. K. Kumar, B. D. Smith, et al. MCL-1 as a Buffer for Proapoptotic BCL-2 Family Members during TRAIL-induced Apoptosis: A MECHANISTIC BASIS FOR SORAFENIB (BAY 43-9006)-INDUCED TRAIL SENSITIZATION J. Biol. Chem., October 12, 2007; 282(41): 29831 - 29846. 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