A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia.
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.
Departments ofBiochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond, VA 23298-0614, USA.
Steven W
SW
Paugh
Barbara S
BS
Paugh
Mohamed
M
Rahmani
Dmitri
D
Kapitonov
Jorge A
JA
Almenara
Tomasz
T
Kordula
Sheldon
S
Milstien
Jeffrey K
JK
Adams
Robert E
RE
Zipkin
Steven
S
Grant
Sarah
S
Spiegel
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000099157:Sphingosine Kinase
D004791:Enzyme Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); D019253:Proto-Oncogene Proteins c-bcl-2; D013110:Sphingosine; D000099157:Sphingosine Kinase