title: Sulindac sulfide suppresses 5-lipoxygenase at clinically relevant concentrations.
abstract: Sulindac is a non-selective inhibitor of cyclooxygenases (COX) used to treat inflammation and pain. Additionally, non-COX targets may account for the drug's chemo-preventive efficacy against colorectal cancer and reduced gastrointestinal toxicity. Here, we demonstrate that the pharmacologically active metabolite of sulindac, sulindac sulfide (SSi), targets 5-lipoxygenase (5-LO), the key enzyme in the biosynthesis of proinflammatory leukotrienes (LTs). SSi inhibited 5-LO in ionophore A23187- and LPS/fMLP-stimulated human polymorphonuclear leukocytes (IC(50) approximately 8-10 microM). Importantly, SSi efficiently suppressed 5-LO in human whole blood at clinically relevant plasma levels (IC(50) = 18.7 microM). SSi was 5-LO-selective as no inhibition of related lipoxygenases (12-LO, 15-LO) was observed. The sulindac prodrug and the other metabolite, sulindac sulfone (SSo), failed to inhibit 5-LO. Mechanistic analysis demonstrated that SSi directly suppresses 5-LO with an IC(50) of 20 muM. Together, these findings may provide a novel molecular basis to explain the COX-independent pharmacological effects of sulindac under therapy.
authors.affiliation: Institute of Pharmaceutical Chemistry/ZAFES, Goethe-University, Max-von-Laue-Str. 9, 60438, Frankfurt/Main, Germany.
authors.forename: Svenja D
authors.initials: SD
authors.lastname: Steinbrink
authors.forename: Carlo
authors.initials: C
authors.lastname: Pergola
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bühring
authors.forename: Sven
authors.initials: S
authors.lastname: George
authors.forename: Julia
authors.initials: J
authors.lastname: Metzner
authors.forename: Astrid S
authors.initials: AS
authors.lastname: Fischer
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Häfner
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Wisniewska
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.forename: Thorsten J
authors.initials: TJ
authors.lastname: Maier
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001769:Blood / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002474:Cell-Free System / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008954:Models, Biological; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009994:Osmolar Concentration; D021381:Protein Transport / Q000187:drug effects; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D000893:Anti-Inflammatory Agents; D002352:Carrier Proteins; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D013467:Sulindac; C025462:sulindac sulfide; D001094:Arachidonate 5-Lipoxygenase