The role of COX-2/COX-3 

Dr Jeremy Cashman

St George’s Hospital, London, UK

 

 

The inhibitory effect of  NSAIDs on the cyclooxygenase enzyme which is required for the conversion of  arachidonic acid  to prostaglandin has been known for some time. However, the identification of two cyclooxygenase isoforms (COX-1 and COX-2) a mere 10 years ago resulted in  the remarkably rapid development of drugs that selectively inhibit COX-2 (coxibs) and recently the even more rapid withdrawal of these drugs due to their unforeseen side effects. This review will summarise our understanding of the COX enzyme system and adverse effects of the coxibs.

 

The enzyme cyclooxygenase (COX) exists in at least 2 isoforms with a wide range of physiological activity:

·        COX-1 (constitutive) involved in platelet production, regulation of renal haemodynamics, electrolyte balance and GI mucosa protection.

·        COX-2 (inducible) upregulated by inflammatory cytokines, endotoxin and mitogens and production of inflammatory prostaglandins (PGs) that mediate pain and oedema. But also constitutive in the CNS and kidneys

 

Trauma results in the release of proinflammatory mediators that induce COX-2, resulting in both peripheral sensitisation of nociceptors, and also secondary sensitisation in the dorsal horn.  COX-2 inhibitors that cross the blood brain barrier potentially reduce central sensitisation. Recently COX-2 has been found to be present in the central nervous system (CNS) when no trauma has occurred. Therefore, it should be considered partly constitutive in that tissue. Huge up-regulation of COX-2 mRNA in the CNS has been found associated with acute and chronic inflammation. A third distinct COX isoenzyme, COX-3, as well as two smaller COX-1-derived proteins (partial COX-1 or PCOX-1a&b proteins), have also been identified. COX-3 is now considered to be a splice variant of COX-1, and is considered to play a key role in the biosynthesis of prostanoids within the central nervous system. COX-3 is weakly sensitive to paracetamol, but this action can only partly explain the analgesic effect of paracetamol.  

 

Prostanoid signal transduction is poorly understood  but it appears that these inflammatory lipids influence cellular physiology by activation of prostanoid receptors (there are 8 types of G-protein-coupled receptors with 7 transmembrane domains), by inactivation of corticosteroid-like receptors and by participation in receptor protein tyrosine kinase signal transduction.

 

All COX inhibitors occupy the arachidonic acid channel of both COX-1 and COX-2. However, aspirin is unique in that it irreversibly acetylates serine-530 of COX-1.  Traditional NSAIDs block both COX-1 and COX-2 by binding to the active site in the C-terminal i.e. they are not selective and can block PGs that have beneficial effects. In contrast, selective COX-2 inhibitors do not bind to the C-terminal active site but bind with the sulphonamide chain in the hydrophilic side pocket of COX-2.  COX-2 is a large molecule and  coxibs demonstrate enhanced binding to the enzyme and stay attached to the COX-2 for longer than the plasma concentrations would indicate. Thus the Coxibs have a longer duration of action than traditional NSAIDs.

 

 

Recent data suggests that NSAIDs are potent antiangiogenics. Angiogenesis, the formation of new capillary blood vessels, is essential  for the growth of solid tumours and wound and  for ulcer healing. Both selective and non selective NSAIDs inhibit angiogenesis through a direct effect on endothelial cells. The anti-angiogenic properties of NSAIDs may contribute to an anticancer effect.

 

Furthermore, it is now known that NSAIDs exhibit significant antinociceptive effects at a spinal level, which does not depend on the existence of a hyperalgesic state. The order of potency for this paradigm is aspirin>indomethcin>rofecoxib> etoricoxib.

 

The first two selective inhibitors of COX-2 (celecoxib and rofecoxib) were approved by the American FDA in 1999 with claims of greater gastrointestinal safety than conventional NSAIDs. It is now apparent that selective COX-2 inhibitors reduce the production of antithrombotic prostacyclin without changing the production of prothrombotic thromboxane and as a result are associated with an increased risk of serious cardiovascular events (APPROVe trial, APC Study, CABG surgery study).  Rofecoxib and valdecoxib have now been withdrawn, lumiracoxib’s launch was abandoned and the prescribing advice for celecoxib and etoricoxib now markedly restricts their indications for use. In the USA naproxen with a proton pump inhibitor is preferred over coxibs by the FDA as first line therapy

 

Further Reading:

Dubois RN, Abramson SB, Crofford L, et al. Cyclooxygenase in biology and disease

            FASEB J 1998; 12: 1063-73

Marnett LJ, Kalgutkar A. Cycooxygenase 2 inhibitors: discovery, selectivity and the

future. TIPS 1999; 20: 465-9

Jones MK, Wang H, Peskar BM, et al. Inhibition of angiogenesis by nonsteroidal anti-

inflammatory drugs: insights into mechanisms and implications for cancer growth and ulcer healing. Nature Medicine 1999; 5: 1418-23

Fitzgerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2.         

N Engl J Med 2001; 345: 433-42

Taking stock of coxibs. Drug Ther Bulletin 2005; 43:1-5

Solomon SD, McMurray JJV, Pfeffer MA, et al. Cardiovascular risk associated with

celecoxib in a clinical trial for colorectal adenoma prevention (APC study). N Engl J Med 2005; 352: 1071-80

Nussmeier  NA, Whelton AA, Brown MT, et al. Complications of the COX-2

inhibitors parecoxib and valdecoxib after cardiac surgery (CABG surgery study). N Engl J Med 2005; 352: 1081-91

Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with

rofecoxib in a colorectal adenoma chemoprevention trial (APPROVe trial). N Engl J Med 2005; 352: 1092-1102

Drazen JM. COX-2 inhibitors – A lesson in unexpected  problems N Engl J Med

2005; 352: 1131-32