A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia

Blood. 2008 Aug 15;112(4):1382-91. doi: 10.1182/blood-2008-02-138958. Epub 2008 May 29.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Leukemia / drug therapy*
  • Mice
  • Mice, SCID
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Sphingosine / analogs & derivatives*
  • Sphingosine / therapeutic use
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Enzyme Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Sphingosine