Distinction of microsomal prostaglandin E synthase-1 (mPGES-1) inhibition from cyclooxygenase-2 inhibition in cells using a novel, selective mPGES-1 inhibitor
| Autor: | Stephen J. Mnich, Olga V. Nemirovskiy, James K. Gierse, Gabriel Mbalaviele, Adele M. Pauley, Alexander F. Shaffer, William M. Moore, Sumathy Mathialagan, Ben S. Zweifel, Jeffrey S. Carter, Jaime L. Masferrer, Michael L. Vazquez, Jane L. Wang |
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| Rok vydání: | 2010 |
| Předmět: |
musculoskeletal diseases
medicine.medical_treatment Immunoblotting Interleukin-1beta Thiazines Gene Expression Prostaglandin Context (language use) Inflammation Pharmacology Carrageenan Prostaglandin E synthase Biochemistry Arthritis Rheumatoid chemistry.chemical_compound Microsomes medicine Animals Humans Cells Cultured Prostaglandin-E Synthases Cyclooxygenase 2 Inhibitors biology Reverse Transcriptase Polymerase Chain Reaction Fibroblasts In vitro Cyclic S-Oxides Rats Intramolecular Oxidoreductases Eicosanoid chemistry Cyclooxygenase 2 biology.protein lipids (amino acids peptides and proteins) Cyclooxygenase medicine.symptom Prostaglandin E |
| Zdroj: | Biochemical Pharmacology. 79:1445-1454 |
| ISSN: | 0006-2952 |
| Popis: | Inflammation-induced microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal enzyme that synthesizes prostaglandin E(2) (PGE(2)) downstream of cyclooxygenase-2 (COX-2). The efficacy of nonsteroidal anti-inflammatory drugs and COX-2 inhibitors in the treatment of the signs and symptoms of osteoarthritis, rheumatoid arthritis and inflammatory pain, largely attributed to the inhibition of PGE(2) synthesis, provides a rationale for exploring mPGES-1 inhibition as a potential novel therapy for these diseases. Toward this aim, we identified PF-9184 as a novel mPGES-1 inhibitor. PF-9184 potently inhibited recombinant human (rh) mPGES-1 (IC(50)=16.5+/-3.8nM), and had no effect against rhCOX-1 and rhCOX-2 (>6500-fold selectivity). In inflammation and clinically relevant biological systems, mPGES-1 expression, like COX-2 expression was induced in cell context- and time-dependent manner, consistent with the kinetics of PGE(2) synthesis. In rationally designed cell systems ideal for determining direct effects of the inhibitors on mPGES-1 function, but not its expression, PF-9184 inhibited PGE(2) synthesis (IC(50) in the range of 0.5-5 microM in serum-free cell and human whole blood cultures, respectively) while sparing the synthesis of 6-keto-PGF(1alpha) (PGF(1alpha)) and PGF(2alpha). In contrast, as expected, the selective COX-2 inhibitor, SC-236, inhibited PGE(2), PGF(1alpha) and PGF(2alpha) synthesis. This profile of mPGES-1 inhibition, distinct from COX-2 inhibition in cells, validates mPGES-1 as an attractive target for therapeutic intervention. |
| Databáze: | OpenAIRE |
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