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, Sarah Spiegel

Research output: Contribution to journalArticlepeer-review

213 Scopus citations

Abstract

The potent bioactive sphingolipid mediator, sphingosine-1-phosphate (S1P), is produced by 2 sphingosine kinase isoen- zymes, 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 leukemicblasts 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.

Original languageBritish English
Pages (from-to)1382-1391
Number of pages10
JournalBlood
Volume112
Issue number4
DOIs
StatePublished - 15 Aug 2008

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