Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic

Abstract

The beneficial actions of nonsteroidal anti-inflammatory drugs (NSAIDs) have been linked to their ability to inhibit inducible COX-2 at sites of inflammation, and their side effects (e.g., gastric damage) to inhibition of constitutive COX-1. Selective inhibitors of COX-2, such as celecoxib, etoricoxib, lumiracoxib, rofecoxib, and valdecoxib have been developed and the greatest recent growth in our knowledge in this area has been come from the clinical use of these compounds. Although clinical data indicate that COX-2 selectivity is associated with a reduction in severe gastrointestinal events, they also reveal there are roles for constitutive COX-2 within tissues such as the brain, kidney, pancreas, intestine, and blood vessels. We now better understand the roles of COX-1 and COX-2 in functions as disparate as the perception of pain and the progression of cancers. Clinical use of COX-2-selective compounds has ignited strong debates regarding potential side effects, most notably those within the cardiovascular system such as myocardial infarctions, strokes, and elevation in blood pressure. This review will discuss how the latest studies help us understand the roles of COX-1 and COX-2 and what clinically proven benefits the newer generation of COX-2-selective inhibitors offer

LY294002 inhibits glucocorticoid-induced COX-2 gene expression in cardiomyocytes through a phosphatidylinositol 3 kinase-independent mechanism

“…In human keratinocytes, PI3K regulates UV-B light induced cyclooxygenase-2 (COX-2) expression through activation of AKT and consequential inhibition of glycogen synthase kinase 3β (GSK3β) (Tang et al, 2001;Bachelor et al, 2005;Sheu et al, 2005;Wu et al, 2005). COX-2 gene responds to a diverse range of stimuli from growth factors or cytokines to physical or chemical stress by increasing expression (Smith, 2000;Hinz and Brune, 2002;Turini and DuBois, 2002;Warner and Mitchell, 2004). Several signaling transduction pathways have been shown to regulate COX-2 gene expression, including the Mitogen-Activated Protein Kinases (Smith, 2000), Protein Kinase A (Choudhary et al, 2004;Pino et al, 2005) or Protein Kinase C (Xuan et al, 2005).…”

Non-steroidal anti-inflammatory drugs in colorectal surgery: A risk factor for anastomotic complications?

“…Several of the classical NSAIDs have been reappraised and turned out to be mostly COX-1 selective, which thus reflected their tendency to cause gastrointestinal side effects. However, the positive effects of selective COX-2 inhibition have subsequently been questioned, as any lesser rate of gastrointestinal adverse effects may have been outweighed by negative effects such as increased risk of cardiovascular events [11] . As regards to colorectal surgery, recent retrospective clinical studies have also indicated a negative effect on anastomotic healing [12][13][14] , as well as some, but not all, experimental investigations [15][16][17] .…”

ISFM and AAFP Consensus Guidelines: Long-Term use of NSAIDs in Cats

“…They exert these effects mostly through inhibiting the production of prostaglandins (PGs) and leukotrienes (LTs) by the cyclo-oxygenase (COX) and 5-lipoxygenase (5-LOX) enzymes, respectively. [33][34][35] Most NSAIDs primarily inhibit the activity of COX enzymes. Although some also inhibit LOX enzymes, for currently licensed feline drugs this is generally short-lived in comparison with COX inhibition, and evidence of additional clinical efficacy from this is lacking.…”

“…[36][37][38] Two distinct COX isoforms (COX-1 and COX-2) have been identified as being responsible for the production of prostaglandins (Fig 7). 35 A third isoform has also been identified, initially known as COX-3, now described as a splice-variant of COX-1, which seems to have a role in the central control of pain. 38 Phospholipase A 2 is the rate-limiting enzyme that initiates the COX pathway by liberating arachidonic acid (AA) from membrane-bound phospholipids.…”

“…35,41 It appears that COX-2 has an important role in healing damaged mucosa in the GI tract, and although COX-2 has been shown to be constitutively expressed in the canine GI tract, 42,43 information on cats is lacking. While COX-1 is the predominant constitutively produced enzyme, COX-2 is predominantly inducible and its production is dramatically upregulated during inflammation, in which it plays a central role.…”