title: Flavocoxid inhibits phospholipase A2, peroxidase moieties of the cyclooxygenases (COX), and 5-lipoxygenase, modifies COX-2 gene expression, and acts as an antioxidant.
abstract: The multiple mechanisms of action for flavocoxid relating to arachidonic acid (AA) formation and metabolism were studied in vitro. Flavocoxid titrated into rat peritoneal macrophage cultures inhibited cellular phospholipase A2 (PLA(2)) (IC(50) = 60 μg/mL). In in vitro enzyme assays, flavocoxid showed little anti-cyclooxygenase (CO) activity on COX-1/-2 enzymes, but inhibited the COX-1 (IC(50) = 12.3) and COX-2 (IC(50) = 11.3 μg/mL) peroxidase (PO) moieties as well as 5-lipoxygenase (5-LOX) (IC(50) = 110 μg/mL). No detectable 5-LOX inhibition was found for multiple traditional and COX-2 selective NSAIDs. Flavocoxid also exhibited strong and varied antioxidant capacities in vitro and decreased nitrite levels (IC(50) = 38 μg/mL) in rat peritoneal macrophages. Finally, in contrast to celecoxib and ibuprofen, which upregulated the cox-2 gene, flavocoxid strongly decreased expression. This work suggests that clinically favourable effects of flavocoxid for management of osteoarthritis (OA) are achieved by simultaneous modification of multiple molecular pathways relating to AA metabolism, oxidative induction of inflammation, and neutralization of reactive oxygen species (ROS).
authors.affiliation: Primus Pharmaceuticals, Inc., 4725 North Scottsdale Road, Scottsdale, AZ 85251, USA. bburnett@primusrx.com
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Burnett
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bitto
authors.forename: Domenica
authors.initials: D
authors.lastname: Altavilla
authors.forename: Francesco
authors.initials: F
authors.lastname: Squadrito
authors.forename: Robert M
authors.initials: RM
authors.lastname: Levy
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Pillai
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism; D002392:Catechin / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004338:Drug Combinations; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007052:Ibuprofen / Q000494:pharmacology; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D010003:Osteoarthritis / Q000188:drug therapy / Q000378:metabolism; D010544:Peroxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D064801:Phospholipase A2 Inhibitors; D054467:Phospholipases A2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D052246:Cyclooxygenase 2 Inhibitors; D004338:Drug Combinations; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D064801:Phospholipase A2 Inhibitors; C544478:flavocoxid; D016718:Arachidonic Acid; D000082:Acetaminophen; D002392:Catechin; D010544:Peroxidases; D001094:Arachidonate 5-Lipoxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat; D054467:Phospholipases A2; D007052:Ibuprofen