Sulindac sulfide suppresses 5-lipoxygenase at clinically relevant concentrations |
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Authors: | Svenja D Steinbrink Carlo Pergola Ulrike Bühring Sven George Julia Metzner Astrid S Fischer Ann-Kathrin Häfner Joanna M Wisniewska Gerd Geisslinger Oliver Werz Dieter Steinhilber Thorsten J Maier |
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Institution: | 1. Institute of Pharmaceutical Chemistry/ZAFES, Goethe-University, Max-von-Laue-Str. 9, 60438, Frankfurt/Main, Germany 3. Department of Pharmaceutical Analytics, Pharmaceutical Institute, University of Tuebingen, Auf der Morgenstelle 8, 72076, Tuebingen, Germany 2. Pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, Theodor Stern Kai 7, 60590, Frankfurt/Main, Germany
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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 (IC50 ≈ 8–10 μM). Importantly, SSi efficiently suppressed 5-LO in human whole blood at clinically relevant plasma levels (IC50 = 18.7 μM). 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 IC50 of 20 μM. Together, these findings may provide a novel molecular basis to explain the COX-independent pharmacological effects of sulindac under therapy. |
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