title: Novel sphingosine kinase-1 inhibitor, LCL351, reduces immune responses in murine DSS-induced colitis.
abstract: Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid metabolite which has been implicated in many diseases including cancer and inflammatory diseases. Recently, sphingosine kinase 1 (SK1), one of the isozymes which generates S1P, has been implicated in the development and progression of inflammatory bowel disease (IBD). Based on our previous work, we set out to determine the efficacy of a novel SK1 selective inhibitor, LCL351, in a murine model of IBD. LCL351 selectively inhibits SK1 both in vitro and in cells. LCL351, which accumulates in relevant tissues such as colon, did not have any adverse side effects in vivo. In mice challenged with dextran sodium sulfate (DSS), a murine model for IBD, LCL351 treatment protected from blood loss and splenomegaly. Additionally, LCL351 treatment reduced the expression of pro-inflammatory markers, and reduced neutrophil infiltration in colon tissue. Our results suggest inflammation associated with IBD can be targeted pharmacologically through the inhibition and degradation of SK1. Furthermore, our data also identifies desirable properties of SK1 inhibitors.
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA; Department of Medicine and the, Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pulkoski-Gross
authors.affiliation: Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Joachim D
authors.initials: JD
authors.lastname: Uys
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: K Alexa
authors.initials: KA
authors.lastname: Orr-Gandy
authors.affiliation: Department of Medicine and the, Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Coant
authors.affiliation: Department of Medicine and the, Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Agnieszka B
authors.initials: AB
authors.lastname: Bialkowska
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Zdzislaw M
authors.initials: ZM
authors.lastname: Szulc
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Aiping
authors.initials: A
authors.lastname: Bai
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Alicja
authors.initials: A
authors.lastname: Bielawska
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Danyelle M
authors.initials: DM
authors.lastname: Townsend
authors.affiliation: Department of Medicine and the, Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
authors.affiliation: Department of Medicine and the, Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA; Northport Veterans Affairs Medical Center, Northport, NY, USA.
authors.forename: Lina M
authors.initials: LM
authors.lastname: Obeid
authors.affiliation: Department of Medicine and the, Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA; Northport Veterans Affairs Medical Center, Northport, NY, USA. Electronic address: ashley.snider@stonybrookmedicine.edu.
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Snider
mesh_terms: D000072283:A549 Cells; D054360:Chemokine CXCL1 / Q000235:genetics; D054426:Chemokine CXCL2 / Q000235:genetics; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D016264:Dextran Sulfate / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D013110:Sphingosine / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D000099157:Sphingosine Kinase
chemical_list: D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D016264:Dextran Sulfate; D006146:Guanidines; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D014409:Tumor Necrosis Factor-alpha; D000099157:Sphingosine Kinase; C000625905:2-N-(1'-carboxamidino)sphingosine
keywords: Inflammation; Inflammatory Bowel Disease; Sphingolipids; Sphingosine 1-Phosphate; Sphingosine Kinase