期刊
CELLULAR AND MOLECULAR LIFE SCIENCES
卷 67, 期 5, 页码 797-806出版社
SPRINGER BASEL AG
DOI: 10.1007/s00018-009-0206-0
关键词
Cyclooxygenase; Leukotrienes; Leukocytes; NSAIDs; Off-target effect
资金
- Landes Offensive zur Entwicklung Wissenschaftlich Okonomischer Exzellenz (LOEWE)
- Lipid Signaling Forschungszentrum Frankfurt (LiFF)
- German Excellence Cluster Cardio-Pulmonary System (ECCPS)
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 a parts per thousand 8-10 mu M). Importantly, SSi efficiently suppressed 5-LO in human whole blood at clinically relevant plasma levels (IC50 = 18.7 mu M). 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 mu M. Together, these findings may provide a novel molecular basis to explain the COX-independent pharmacological effects of sulindac under therapy.
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