krp-203 and sphingosine-1-phosphate

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many critical cellular processes including proliferation, survival, and migration, as well as angiogenesis and allergic responses. S1P levels inside cells are tightly regulated by the balance between its synthesis by sphingosine kinases and degradation. S1P is interconvertible with ceramide, which is a critical mediator of apoptosis. It has been postulated that the ratio between S1P and ceramide determines cell fate. Activation of sphingosine kinase by a variety of agonists increases intracellular S1P, which in turn can function intracellularly as a second messenger or be secreted out of the cell and act extracellularly by binding to and signaling through S1P receptors in autocrine and/or paracrine manners. Recent studies suggest that this "inside-out" signaling by S1P may play a role in many human diseases, including cancer, atherosclerosis, inflammation, and autoimmune disorders such as multiple sclerosis. In this review we summarize metabolism of S1P, mechanisms of sphingosine kinase activation, and S1P receptors and their downstream signaling pathways and examine relationships to multiple disease processes. In particular, we describe recent preclinical and clinical trials of therapies targeting S1P signaling, including 2-amino-2-propane-1,3-diol hydrochloride (FTY720, fingolimod), S1P receptor agonists, sphingosine kinase inhibitors, and anti-S1P monoclonal antibody.

Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Apoptosis; Enzyme Activation; Fingolimod Hydrochloride; Humans; Hypersensitivity; Immunosuppressive Agents; Lysophospholipids; Multiple Sclerosis; Neoplasms; Phosphotransferases (Alcohol Group Acceptor); Propylene Glycols; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Sulfhydryl Compounds

The recent identification of a cellular balance between ceramide and sphingosine 1-phosphate (S1P) as a critical regulator of cell growth and death has stimulated increasing research effort to clarify the role of ceramide and S1P in various diseases associated with dysregulated cell proliferation and apoptosis. S1P acts mainly, but not exclusively, by binding to and activating specific cell surface receptors, the so-called S1P receptors. These receptors belong to the class of G protein-coupled receptors that constitute five subtypes, denoted as S1P(1)-S1P(5), and represent attractive pharmacological targets to interfere with S1P action. Whereas classical receptor antagonists will directly block S1P action, S1P receptor agonists have also proven useful, as recently shown for the sphingolipid-like immunomodulatory substance FTY720. When phosphorylated by sphingosine kinase to yield FTY720 phosphate, it acutely acts as an agonist at S1P receptors, but upon prolonged presence, it displays antagonistic activity by specifically desensitizing the S1P(1) receptor subtype. This commentary will cover the most recent developments in the field of S1P receptor pharmacology and highlights the potential therapeutic benefit that can be expected from these novel drug targets in the future.

Topics: Animals; Fingolimod Hydrochloride; Humans; Lysophospholipids; Oxadiazoles; Phosphotransferases (Alcohol Group Acceptor); Propylene Glycols; Pyrazoles; Pyridines; Receptors, Lysosphingolipid; Sphingosine; Sulfhydryl Compounds; Thiazolidines; Thiophenes

Sphingosine 1 phosphate [S1P] is a bioactive lipid mediator involved in the regulation of several cellular processes though the activation of a G protein-coupled receptor family known as the S1P receptors [S1PRs]. Advances in the understanding of the biological activities mediated by S1PRs have sparked great interest in the S1P/S1PRs axes as new therapeutic targets for the modulation of several cellular processes. In particular, the S1P/S1PR1 axis has been identified as key regulator for lymphocyte migration from lymph nodes. The blockade of this axis is emerging as a new therapeutic approach to control the aberrant leukocyte migration into the mucosa in inflammatory bowel disease [IBD]. This review briefly summarises the current evidence coming from clinical studies, and discusses the future prospects of S1P inhibitors for treatment of inflammatory bowel disease.

Topics: Animals; Camphanes; Cell Movement; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Indans; Inflammatory Bowel Diseases; Leukocytes; Lysophospholipids; Molecular Targeted Therapy; Oxadiazoles; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Sulfhydryl Compounds; Sulfonamides