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

• Published in: Blood Vol. 112; no. 4; pp. 1382 - 1391
• Main Authors: Paugh, Steven W., Paugh, Barbara S., Rahmani, Mohamed, Kapitonov, Dmitri, Almenara, Jorge A., Kordula, Tomasz, Milstien, Sheldon, Adams, Jeffrey K., Zipkin, Robert E., Grant, Steven, Spiegel, Sarah
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.08.2008; The Americain Society of Hematology; American Society of Hematology
• Series: Neoplasia
• Subjects: Animals; Apoptosis - drug effects; Biological and medical sciences; Cell Proliferation - drug effects; Enzyme Inhibitors - therapeutic use; Hematologic and hematopoietic diseases; Humans; Leukemia - drug therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Mice, SCID; Neoplasia; 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; Human; Targeting; Hematology; Targeted therapy; Leukemia; Malignant hemopathy; Inhibitor; Sphingosine kinase 1; Cancer
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-02-138958

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.