|
|
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.
 Previous Article | Next Article 
Submitted February 13, 2008
Accepted May 3, 2008
A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia
Steven W Paugh, Barbara S Paugh, Mohamed Rahmani, Dmitri Kapitonov, Jorge A Almenara, Tomasz Kordula, Sheldon Milstien, Jeffrey K Adams, Robert E Zipkin, Steven Grant, and Sarah Spiegel*
Biochemistry and Molecular Biology, VCU, Richmond, VA, United States
Medicine, VCU, Richmond, VA, United States
Intramural Research Program, National Institute of Mental Health, Bethesda, MD, United States
BIOMOL International, Plymouth Meeting, PA, United States
* Corresponding author; email: sspiegel{at}vcu.edu.
The potent bioactive sphingolipid mediator, sphingosine-1-phosphate (S1P), is produced by two sphingosine kinase isoenzymes, SphK1 and SphK2. Expression of SphK1 is upregulated 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, isozyme-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, 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 pro-apoptotic 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 to 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:
|
|
|
|
 
D. Kapitonov, J. C. Allegood, C. Mitchell, N. C. Hait, J. A. Almenara, J. K. Adams, R. E. Zipkin, P. Dent, T. Kordula, S. Milstien, et al.
Targeting Sphingosine Kinase 1 Inhibits Akt Signaling, Induces Apoptosis, and Suppresses Growth of Human Glioblastoma Cells and Xenografts
Cancer Res.,
September 1, 2009;
69(17):
6915 - 6923.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
