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

• Published in: Biochimica et biophysica acta 2013-01, Vol.1831 (1), p.157-166
• Main Authors: Orr Gandy, K. Alexa, Obeid, Lina M.
• Format: Article
• Language: English
• Subjects: Animals; atherosclerosis; bioactive properties; Biomarker; cell movement; cells; Disease; distress; enzyme inhibitors; Humans; immunity; inflammation; Inhibitor; Lysophospholipids - metabolism; metabolites; metastasis; Molecular Targeted Therapy; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors; Phosphotransferases (Alcohol Group Acceptor) - metabolism; plasma membrane; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; signal transduction; Signal Transduction - drug effects; Sphingolipid; sphingolipids; sphingosine; Sphingosine - analogs & derivatives; Sphingosine - metabolism; Sphingosine 1-phosphate (S1P); Sphingosine kinase (SK)
• ISSN: 1388-1981; 0006-3002; 1879-2618
• DOI: 10.1016/j.bbalip.2012.07.002

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 20years 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. This article is part of a Special Issue entitled Advances in Lysophospholipid Research. ► The SK/S1P pathway is dysregulated in numerous pathologies and disease states. ► Only recently have potent and specific inhibitors of SK begun to be developed. ► Further development of SK inhibitors may provide novel disease treatments.