Targeting the sphingosine kinase/sphingosine 1-phosphate pathway in disease: Review of sphingosine kinase inhibitors

Abstract

Sphingosine 1-phosphate (S1P) is an important bioactive sphingolipid metabolite that has been implicated in numerous physiological and cellular processes. Not only does S1P play a structural role in cells by defining the components of the plasma membrane, but in the last 20 years it has been implicated in various significant cell signaling pathways and physiological processes: for example, cell migration, survival and proliferation, cellular architecture, cell-cell contacts and adhesions, vascular development, atherosclerosis, acute pulmonary injury and respiratory distress, inflammation and immunity, and tumorogenesis and metastasis [1, 2]. Given the wide variety of cellular and physiological processes in which S1P is involved, it is immediately obvious why the mechanisms governing S1P synthesis and degradation, and the manner in which these processes are regulated, are necessary to understand. In gaining more knowledge about regulation of the Sphingosine Kinase (SK)/S1P pathway, many potential therapeutic targets may be revealed. This review explores the roles of the SK/S1P pathway in disease, summarizes available SK enzyme inhibitors and examines their potential as therapeutic agents.

The Apoptotic Mechanism of Action of the Sphingosine Kinase 1 Selective Inhibitor SKI-178 in Human Acute Myeloid Leukemia Cell Lines

“…Elevated expression of SphK1 has consistently been observed in various cancer types, including leukemia (Heffernan-Stroud and Obeid, 2013), and has become a promising target for novel therapeutic strategies (Orr Gandy and Obeid, 2013). We previously established SKI-178 as a potent selective inhibitor of SphK1 through in vitro activity assays with purified SphK1 protein (Hengst et al, 2010).…”

The Role of Sphingolipids in Arachidonic Acid Metabolism

“…The S1P family of G protein-coupled receptors, of which there are five (S1P 1 -S1P 5 ), couple to different alpha subunits of heterotrimeric G proteins such as Ga i , Ga q , and Ga 12/13 . S1P receptor expression patterns, along with the Ga subunits to which each receptor couples, dictate the activation of different downstream targets that occur upon receptor activation, including the activation of Rac, extracellular signal-regulated kinase, phosphatidylinositol-3 kinase, adenylyl cyclase, phospholipase C, Rho, and c-jun N-terminal kinase, resulting in various cellular responses (16).…”

Original article The key role of sphingosine kinases in the molecular mechanism of neuronal cell survival and death in an experimental model of Parkinson’s disease

“…Sphks are crucial enzymes in maintaining a balance between the lipid signalling molecules, such as ceramide/sphingosine, and S1P [36,37,50,53]. Sphk1 and Sphk2 share overall homology and synthesize S1P, which depending on intracellular localisations of Sphks isoforms plays different roles within the cell [36,50,55].…”

“…The level of intracellular S1P is regulated not only by Sphks but also by enzymes involved in its degradation, that means by S1P lyase (SPL) and by specific S1P phosphatase (SPP1) and also by less-specific SPP2 and other phosphatases ( Fig. 1) [36,37]. S1P formed at the plasma membrane can be easily exported from the cell and can act in an autocrine or paracrine fashion through five specific G protein-coupled receptors (S1P1-S1P5), located in sphingolipid microdomains of cell membranes [49].…”