By Steven Grant, MD

2009-01-01

Dr. Grant indicated no relevant conflicts of interest.

Paugh SW, Paugh BS, Rahmani M, et al. A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia. Blood. 2008;112:1382-91.

Lipid mediators have long been known to play important roles in diverse cellular processes in both normal and neoplastic cells, particularly regulation of survival and cell death. For example, the lipid second messenger ceramide has been implicated in promoting leukemic cell death, including that triggered by conventional cytotoxic agents, including ara-C and anthracyclines, as well as that induced by novel targeted agents, including histone deacetylase inhibitors. Alterations in lipid signaling pathways have also been invoked to explain certain forms of drug resistance in leukemia (e.g., anthracycline resistance). Such considerations have prompted intense interest in agents that modulate lipid signaling pathways in transformed cells and lower the apoptotic threshold.

Sphingosine-1-phosphate (S1P) is a lipid mediator, derived from the precursors ceramide and sphingosine, which exerts potent anti-apoptotic effects. The sphingosine/ceramide rheostat is regulated in part by the enzyme sphingosine kinase 1 (SphK1), which is up-regulated in several malignant diseases including leukemia. Efforts to target this enzyme, and the pathways it regulates, have been complicated by the fact that most SphK1 inhibitors developed to date are relatively non-specific (i.e., they also target SphK2, an enzyme that exerts certain actions that may oppose those of SphK2). For example, safingol and dimethylsphingosine (DMS) have been shown to induce leukemic cell death, but as both agents inhibit SphK1 and K2, the mechanism by which these agents act is unclear.

New insights into this question have emerged from a recent study by Paugh and colleagues. Through a broad screening approach, they identified a highly specific, water-soluble inhibitor of SphK1, designated SK1-I, which potently induced apoptosis in human leukemia cell lines and primary blasts, and inhibited the growth of leukemic cells in nude mice, but was relatively sparing to normal hematopoietic cells. Notably, SK1-I diminished expression of S1P, while reciprocally increasing expression of its pro-apoptotic precursor ceramide. Significantly, SK1-I lethality was sharply attenuated by S1P, arguing that modulating the ceramide/S1P rheostat played a clear functional role in triggering leukemic cell death. The authors conclude that SphK1 activation is important for leukemia cell survival and that targeting this protein warrants attention as a novel anti-leukemic strategy.

The significance of this study is that while targeting signaling pathways implicated in leukemogenesis, such as those related to mutated receptor-tyrosine kinases (e.g., FLT3), has received considerable attention, efforts to disrupt critical lipid signaling survival pathways remain relatively unexplored. However, this situation appears to be changing. For example, several recent studies have suggested a role for the S1P kinase and protein phosphatase 2A (PP2A) activator FTY720, an immunosuppressant, in CML and CLL.^{1, 2} Whether specific agents such as SK1-I will offer therapeutic advantages in leukemia compared to agents such as FTY720, which are considerably more pleiotropic in their actions, remains to be determined. Whatever the answer to this question, the development of new and selective inhibitors of critical lipid signaling pathways could potentially add potent new weapons to the expanding therapeutic armamentarium in acute and chronic leukemia.

References

1. Neviani P, Santhanam R, Oaks JJ, et al. FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia. J Clin Invest. 2007;117:2408-21.

2. Liu Q, Zhao X, Frissora F, et al. FTY720 demonstrates promising preclinical activity for chronic lymphocytic leukemia and lymphoblastic leukemia/lymphoma. Blood. 2008;111:275-84.

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