SEARCH:   Advanced

Blood, 15 August 2008, Vol. 112, No. 4, pp. 1382-1391. Prepublished online as a Blood First Edition Paper on May 29, 2008; DOI 10.1182/blood-2008-02-138958. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-02-138958v1 112/4/1382    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 Paugh, S. W. Articles by Spiegel, S. Search for Related Content PubMed PubMed Citation Articles by Paugh, S. W. Articles by Spiegel, S. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia Steven W. Paugh1, Barbara S. Paugh1, Mohamed Rahmani2, Dmitri Kapitonov1, Jorge A. Almenara2, Tomasz Kordula1, Sheldon Milstien3, Jeffrey K. Adams4, Robert E. Zipkin4, Steven Grant2, and Sarah Spiegel1 Departments of1 Biochemistry and Molecular Biology and 2 Medicine, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond; 3 National Institute of Mental Health, Bethesda, MD; and 4 BIOMOL International, Plymouth Meeting, PA The potent bioactive sphingolipid mediator, sphingosine-1-phosphate (S1P), is produced by 2 sphingosine kinase isoenzymes, SphK1 and SphK2. Expression of SphK1 is up-regulated in cancers, including leukemia, and associated with cancer progression. A screen of sphingosine analogs identified (2R,3S,4E)-N-methyl-5-(4'-pentylphenyl)-2-aminopent-4-ene-1,3-diol, designated SK1-I (BML-258), as a potent, water-soluble, isoenzyme-specific inhibitor of SphK1. In contrast to pan-SphK inhibitors, SK1-I did not inhibit SphK2, PKC, or numerous other protein kinases. SK1-I decreased growth and survival of human leukemia U937 and Jurkat cells, and enhanced apoptosis and cleavage of Bcl-2. Lethality of SK1-I was reversed by caspase inhibitors and by expression of Bcl-2. SK1-I not only decreased S1P levels but concomitantly increased levels of its proapoptotic precursor ceramide. Conversely, S1P protected against SK1-I–induced apoptosis. SK1-I also induced multiple perturbations in activation of signaling and survival-related proteins, including diminished phosphorylation of ERK1/2 and Akt. Expression of constitutively active Akt protected against SK1-I–induced apoptosis. Notably, SK1-I potently induced apoptosis in leukemic blasts isolated from patients with acute myelogenous leukemia but was relatively sparing of normal peripheral blood mononuclear leukocytes. Moreover, SK1-I markedly reduced growth of AML xenograft tumors. Our results suggest that specific inhibitors of SphK1 warrant attention as potential additions to the therapeutic armamentarium in leukemia. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Maceyka, S. Milstien, and S. Spiegel Sphingosine-1-phosphate: the Swiss army knife of sphingolipid signaling J. Lipid Res., April 1, 2009; 50(Supplement): S272 - S276. [Abstract] [Full Text] [PDF] B. S. Paugh, L. Bryan, S. W. Paugh, K. M. Wilczynska, S. M. Alvarez, S. K. Singh, D. Kapitonov, H. Rokita, S. Wright, I. Griswold-Prenner, et al. Interleukin-1 Regulates the Expression of Sphingosine Kinase 1 in Glioblastoma Cells J. Biol. Chem., February 6, 2009; 284(6): 3408 - 3417. [Abstract] [Full Text] [PDF]

	Copyright © 2008 by American Society of Hematology         Online ISSN: 1528-0020