Advances in the pharmacology of cyclooxygenase

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1 Chinese Bulletin of Life Sciences Vol. 17, No.3 Jun., (2005) (cyclooxygenase COX) (prostaglandins PGs) COX COX-1 COX-2 COX-1 COX-2 Q55 A Advances in the pharmacology of cyclooxygenase ZHANG Wei-Yu, ZHU Xing-Zu* (Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of CAS, Shanghai , China) Abstract: Cyclooxygenase (COX), a rate-limited enzyme in arachidonic acid metabolic pathways, can catalyse the synthesis of cyclic endoperoxides from arachidonic acid to form prostaglandins (PGs). Two cyclooxygenase isoforms have been identified and referred to as constitutive COX-1 and inducible COX-2. According to a popular hypothesis, COX-1 generates good prostaglandins for physiological housekeeping functions, while COX-2 forms the bad prostaglandins responsible for inflammatory symptoms. However, recent data show that the biological functions of prostanoids formed by the two enzymes are much more complex and interrelated than previously appreciated. The objective of the article is to provide an overview of recent developments in the field about the role of COX in various diseases, and to discuss the feasibility as a potential target for therapeutic treatment. Key words: cyclooxygenase; prostaglandins; inflammation; neurodegenerative disease; cardiovascular disease; cancer; non-steroidal anti-inflammatory drugs (COX)(prostaglandins, PGs) (thromboxane, TX) COX (1) G 2 (PGG 2 ); (2) PGG 2 H 2 (PGH 2 ) COX COX-1 COX-2 COX-1 COX-2 COX No. 04DZ14005 (1973 ) (1946 ) *

2 232 COX-2 (nonsteroidal anti-inflammatory drugs, NSAIDs) COX NSAIDs COX-1 COX-2 COX-1 NSAIDs NSAIDs COX-2 celecoxib rofecoxib COX-1 COX-2 [1] COX 1 COX COX-2 COX-2 COX-2 [2] celecoxib COX-1 [3] COX-1 [4 8] COX-2 E 2 (PGE 2 ) COX-1 COX-2 COX-1 COX-2 COX-1 COX COX-2 [9] COX-2 2 h 48 h 2 h 3.5 PGE 2 48 h 15- deoxy-d PGJ 2 COX-2 2 h 48 h COX-2 2 COX COX-1 PG (LPS) -1(IL-1) COX-2 PGE 2 [10 11] COX-2 NSAIDs (Alzheimer s disease, AD) [12] COX-2 [13] AD COX-2 β- (β-amyloid, Aβ) SH-SY5Y COX-2 [14] (1-methyl- 4-phenyl-1,2,3,6- tetrahydropyridine, MPTP) COX-2 JNK/c-Jun [15] COX-2 COX-2 (reactive oxygenase species, ROS) [16] ROS (Parkinson s disease, PD) ROS COX-2 D 2 (PGD 2 ) J 2 (PGJ 2 ) COX-2 [17] PGJ 2

3 233 [18] COX-2 COX-2 COX-2 MPTP PD [19] COX NSAIDs AD [20] NSAIDs (ibuprofen) (indomethacin) Aβ42 [21] COX PGE 2 Aβ NSAIDs γ- (γ-secretase) [22] COX-2 3 COX (atherosclerosis) COX-1 A 2 (TXA 2 ) COX-2 I 2 (PGI 2 ) [23] COX-1 TXA 2 PGI 2 COX-2 PGI 2 TXA 2 COX-2 PGI 2 PGE 2 [24] Baker [25] / COX-2 COX-2 COX-2 apoe [26] [27] (LDL) X (LXR) COX-2 [28~29] COX-2 COX-2 TXA 2 COX-2 [30] 4 COX COX-2 COX-1 COX-2 mrna [31] C(PKC) Ras COX-2 AP-1 NF-IL6 NF-κB NFAT PEA3 COX-2 TATA TATA (TATA box) p53 COX-2 [32] p53 COX-2 COX-2 COX-2 COX-2 mrna 3' AU (AU-enriched elements) COX-2 mrna COX-2 mrna COX-2 mrna [31] COX-2 COX-2 COX-2 [32] COX-2 [33] COX-2 (knock out) COX-2 COX-1 [34~35] COX-2 COX-2 COX-2 COX-2

4 234 COX-2 COX COX-1 COX-2 COX-1 COX-2 [1] Funk C D. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science, 2001, 294: 1871~1875 [2] Nantel F, Denis D, Gordon R, et al. Distribution and regulation of cyclooxygenase-2 in carrageenan-induced inflammation. Br J Pharmacol, 1999, 128: 853~859 [3] Anderson G D, Hauser S D, McGarity K L, et al. Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis. J Clin Invest, 1996, 97: 2672~2679 [4] Smith C J, Zhang Y, Koboldt C M, et al. Pharmacological analysis of cyclooxygenase-1 in inflammation. Proc Natl Acad Sci USA, 1998, 95: 13313~13318 [5] Wallace J L, Chapman K, McKnight W. Limited anti-inflammatory efficacy of cyclooxygenase-2 inhibition in carrageenan-airpouch inflammation. Br J Pharmacol, 1999, 126: 1200~1204 [6] Wallace J L, Bak A, McKnight W, et al. Cyclooxygenase 1 contributes to inflammatory responses in rats and mice: implications for gastrointestinal toxicity. Gastroenterology, 1998, 115: 101~109 [7] Langenbach R, Morham S G, Tiano H F, et al. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acidinduced inflammation and indomethacin-induced gastric ulceration. Cell, 1995, 83: 483~492 [8] Ochi T, Goto T. Differential effect of FR122047, a selective cyclooxygenase-1 inhibitor, in rat chronic models of arthritis. Br J Pharmacol, 2002, 135: 782~788 [9] Gilroy D W, Colville-Nash P R, Willis D, et al. Inducible cyclooxygenase may have anti-inflammatory properties. Nat Med, 1999, 5: 698~701 [10] Beiche F, Scheuerer S, Brune K, et al. Upregulation of cyclooxygenase-2 mrna in the rat spinal cord following peripheral inflammation. FEBS Lett, 1996, 390: 165~169 [11] Cao C, Matsumura K, Yamagata K, et al. Endothelial cells of the brain vasculature express COX-2 mrna in response to systemic interleukin-1: a possible site of prostaglandin synthesis responsible for fever. Brain Res, 1996, 733: 263~272 [12] McGeer P L, Schulzer M, McGeer E G. Arthritis and antiinflammatory agents as possible protective factors for Alzheimer s disease: a review of 17 epidemiologic studies. Neurology, 1996, 47: 425~432 [13] Tocco G, Freire O, Schreiber S S, et al. Maturational regulation and regional induction of cyclooxygenase-2 in rat brain: implications for Alzheimer s disease. Expl Neurol, 1997, 144: 339~349 [14] Pasinetti G M, Aisen P S. Cyclooxygenase-2 expression is increased in frontal cortex of Alzheimer s disease brain. Neuroscience, 1998, 87(2): 319~324 [15] Teismann P, Tieu K, Choi D K, et al. Cyclooxygenase-2 is instrumental in Parkinson s disease neurodegeneration. Proc Natl Acad Sci USA, 2003, 100: 5473~5478 [16] Sairanen T, Ristimaki A, Karjalainen-Lindsberg M L, et al. Cyclooxygenase-2 is induced globally in infarcted human brain. Ann Neurol, 1998, 43: 738~747 [17] Li Z, Jansen M, Ogburn K, et al. Neurotoxic prostaglandin J 2 enhances cyclooxygenase-2 expression in neuronal cells through the p38mapk pathway: A death wish? J Neurosci Res, 2004, 78(6): 824~836 [18] Kondo M, Oya-Ito T, Kumagai T, et al. Cyclopentenone prostaglandins as potential inducers of intracellular oxidative stress. J Biol Chem, 2001, 276: 12076~12083 [19] Teismann P, Ferger B. Inhibition of the cyclooxygenase isoenzymes COX-1 and COX-2 provide neuroprotection in the MPTP-mouse model of Parkinson s disease. Synapse, 2001, 39: 167~174 [20] Zandi P P, Anthony J C, Hayden K M, et al. Reduced incidence of AD with NSAID but not H 2 receptor antagonists: the cache county study. Neurology, 2002, 59: 880~886 [21] Weggen S, Eriksen J L, Das P, et al. A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature, 2001, 414: 212~216 [22] Qin W P, Ho L, Pompl P N, et al. Cyclooxygenase (COX)- 2 and COX-1 potentiate β-amyloid peptide generation through mechanisms that involve γ-secretase activity. J Biol Chem, 2003, 278: 50970~50977 [23] McAdam B F, Catella-Lawson F, Mardini I A, et al. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA, 1999, 96: 272~277 [24] Adderley S R, Fitzgerald D J. Oxidative damage of cardiomyocytes is limited by extracellular regulated kinases 1/2-mediated induction of cyclooxygenase-2. J Biol Chem. 1999, 274: 5038~5046 [25] Baker C S, Hall R J, Evans T J, et al. Cyclooxygenase-2 is widely expressed in atherosclerotic lesions affecting native and transplanted human coronary arteries and colocalizes with inducible nitric oxide synthase and nitrotyrosine particularly in macrophages. Arterioscler Thromb Vasc Biol, 1999, 19: 646~655 [26] Burleigh M E, Babaev V R, Oates J A, et al. Cyclooxygenase- 2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice. Circulation, 2002, 105: 1816~1823 [27] Bea F, Blessing E, Bennett B J, et al. Chronic inhibition of cyclooxygenase-2 does not alter plaque composition in a

5 235 mouse model of advanced unstable atherosclerosis. Cardiovasc Res, 2003, 60: 198~204 [28] Eligini S, Brambilla M, Banfi C, et al. Oxidized phospholipids inhibit cyclooxygenase-2 in human macrophages via nuclear factor-kb/iκb- and ERK2-dependent mechanisms. Cardiovasc Res, 2002, 55: 406~415 [29] Banfi C, Colli S, Eligini S, et al. Oxidized LDLs influence thrombotic response and cyclooxygenase 2. Prostaglandins Leukot Essent Fatty Acids, 2002, 67: 169~173 [30] Ray W A, Stein C M, Daugherty J R, et al. COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet, 2002, 360: 1071~1073 [31] Dixon D A, Kaplan C D, McIntyre T M, et al. Posttranscriptional control of cyclooxygenase-2 gene expression. J Biol Chem, 2000, 275: 11750~11757 [32] Liu C H, Chang S H, Narko K, et al. Over-expression of cyclooxygenase (Cox)-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem, 2001, 276: 18563~18569 [33] Neufang G, Fürstenberger G, Heidt M, et al. Abnormal differentiation of epidermis in transgenic mice constitutively expressing cyclooxygenase-2 in skin. Proc Natl Acad Sci USA, 2001, 98: 7629~7634 [34] Chulada P C, Thompson M B, Mahler J F, et al. Genetic disruption of Ptgs-1, as well as Ptgs-2, reduces intestinal tumorigenesis in Min mice. Cancer Res, 2000, 60: 4705~4708 [35] Tiano H F, Loftin C D, Akunda J, et al. Deficiency of either cyclooxygenase (COX)-1 or COX-2 alters epidermal differentiation and reduces mouse skin tumorigenesis. Cancer Res, 2002, 62: 3395~3401 SARS http: //

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