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.
Paugh
Steven W
SW
Departments ofBiochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond, VA 23298-0614, USA.
Paugh
Barbara S
BS
Rahmani
Mohamed
M
Kapitonov
Dmitri
D
Almenara
Jorge A
JA
Kordula
Tomasz
T
Milstien
Sheldon
S
Adams
Jeffrey K
JK
Zipkin
Robert E
RE
Grant
Steven
S
Spiegel
Sarah
S
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