MK-886, an inhibitor of the 5-lipoxygenase-activating protein, inhibits cyclooxygenase-1 activity and suppresses platelet aggregation

• Published in: European journal of pharmacology 2009-04, Vol.608 (1), p.84-90
• Main Authors: Koeberle, Andreas, Siemoneit, Ulf, Northoff, Hinnak, Hofmann, Bettina, Schneider, Gisbert, Werz, Oliver
• Format: Article
• Language: English
• Subjects: 5-Lipoxygenase; Animals; Biological and medical sciences; Cell Line, Tumor; Cyclooxygenase; Cyclooxygenase 1 - isolation & purification; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - isolation & purification; Cyclooxygenase 2 - metabolism; Dose-Response Relationship, Drug; Humans; Hydrogen Bonding; Indoles - chemistry; Indoles - pharmacology; Inhibitory Concentration 50; Leukotriene; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - pharmacology; Lung Neoplasms - pathology; Medical sciences; MK-886; Models, Chemical; Molecular Structure; Pharmacology. Drug treatments; Platelet aggregation; Platelet Aggregation Inhibitors - pharmacology; Prostaglandin; Recombinant Proteins - isolation & purification; Recombinant Proteins - metabolism; Sheep
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2009.02.023

MK-886, an inhibitor of the 5-lipoxygenase-activating protein (FLAP), potently suppresses leukotriene biosynthesis in intact cells and is frequently used to define a role of the 5-lipoxygenase (EC 1.13.11.34) pathway in cellular or animal models of inflammation, allergy, cancer, and cardiovascular disease. Here we show that MK-886 also interferes with the activities of cyclooxygenases (COX, EC 1.14.99.1). MK-886 inhibited isolated COX-1 (IC 50 = 8 µM) and blocked the formation of the COX-1-derived products 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid (12-HHT) and thromboxane B 2 in washed human platelets in response to collagen as well as from exogenous arachidonic acid (IC 50 = 13–15 µM). Isolated COX-2 was less affected (IC 50 = 58 µM), and in A549 cells, MK-886 (33 µM) failed to suppress COX-2-dependent 6-keto-prostaglandin (PG)F 1α formation. The distinct susceptibility of MK-886 towards COX-1 and -2 is apparent in automated molecular docking studies that indicate a preferred binding of MK-886 to COX-1 into the active site. MK-886 (10 µM) inhibited COX-1-mediated platelet aggregation induced by collagen or arachidonic acid whereas thrombin- or U-46619-induced (COX-independent) aggregation was not affected. Since leukotrienes and prostaglandins share (patho)physiological properties in the development and regulation of carcinogenesis, inflammation, and vascular functions, caution should be used when interpreting data where MK-886 is used as tool to determine the involvement of FLAP and/or the 5-lipoxygenase pathway in respective experimental models.