Aspirin and Other Cyclooxygenase Inhibitors: New Therapeutic Insights

Kenneth K. Wu

doi:10.1055/s-2003-40668

Seminars in Vascular Medicine, Table of Contents

Semin Vasc Med 2003; 03(2): 107-112
DOI: 10.1055/s-2003-40668

Aspirin and Other Cyclooxygenase Inhibitors: New Therapeutic Insights

Kenneth K. Wu

Vascular Biology Research Center and Division of Hematology, The University of Texas-Houston Health Science Center, Houston, TX

Abstract

ABSTRACT

Aspirin acetylates serine-530 of cyclooxygenase-1 (COX-1), thereby blocking thromboxane A₂ synthesis in platelets and reducing platelet aggregation. This mechanism of action accounts for the effect of aspirin on prevention of coronary artery and cerebrovascular thrombosis. Aspirin is less effective in inhibiting COX-2 activity, whereas celecoxib and rofecoxib selectively inhibit COX-2 activity as they contain a side chain to anchor to the side pocket of COX-2 substrate channel. Aspirin and salicylate at therapeutic concentrations inhibit COX-2 protein expression through interference with binding of CCAAT/enhancer binding protein β (C/EBPβ) to its cognate site on COX-2 promoter/enhancer. Expression of other genes, such as inducible nitric oxide synthase and interleukin-4, may be inhibited by aspirin and salicylate by a C/EBP-dependent mechanism. Aspirin at suprapharmacological concentrations inhibits NF-κB-mediated gene transcription and protects tissue from injury. These recent studies provide new insight into the pharmacological actions of aspirin and salicylate preparations and implicate C/EBPβ as a potential target for therapy of inflammation and tissue injury.

KEYWORDS

Aspirin - cyclooxygenase - C/EBP-mediated gene transcription

Full Text

References

REFERENCES

1 Wu K K. Inducible cyclooxygenase and nitric oxide synthase. Adv Pharmacol . 1995; 33 179-207
2 Vane J R, Mitchell J A, Appleton I. Inducible isoforms of cyclooxygenase and nitric oxide synthase in inflammation. Proc Natl Acad Sci USA . 1994; 91 2046-2050
3 Tsujii M, Kawano S, DuBois R N. Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA . 1997; 94 3336-3340
4 Seibert K, Zhang Y, Leahy Y. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA . 1994; 91 12013-12017
5 Meade E A, Smith W L, DeWitt D L. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other nonsteroidal anti-inflammatory drugs. J Biol Chem . 1993; 268 6610-6614
6 Gupta R A, DuBois R N. Aspirin, NSAIDs and colon cancer prevention. Gastroenterology . 1998; 114 1095-1100
7 Lipsky P E, Isakson P C. Outcome of specific COX-2 inhibition in rheumatoid arthritis. J Rheumatol . 1997; 24 9-14
8 Kurumbail R G, Stevens A M, Gierse J K. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature . 1996; 384 644-648
9 Bensen W G, Zhao S Z, Burke T A. Upper gastro-intestinal tolerability of celecoxib, a COX-2 specific inhibitor compared to naproxen and placebo. J Rheumatol . 2000; 27 1876-1883
10 Day R, Morrison B, Luza A, for the Rofecoxib/buprofen comparator study group. A randomized trial of the efficacy and tolerability of the COX-2 inhibitor rofecoxib vs. ibuprofen in patients with osteoarthritis. Arch Intern Med . 2000; 160 1781-1787
11 Mukherjee D, Nissen S E, Topel E J. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA . 2001; 286 954-959
12 Dowd N P, Scully M, Adderley S R. Inhibition of cyclooxygenase-2 aggravates cloxorubicin-mediated cardiac injury in vivo. J Clin Invest . 2001; 108 585-590
13 Muscara M N, Vergnolle N, Lovren F. Selective cyclooxygenase-2 inhibition with celecoxib elevates blood pressure and promotes leukocyte adherence. Br J Pharmacol . 2000; 129 1423-1430
14 Zembowicz A, Jones S L, Wu K K. Induction of cyclooxygenase 2 in human umbilical vein endothelial cells by lysophosphatidylcholine. J Clin Invest . 1995; 96 1688-1692
15 Roth G J, Majerus P W. The mechanism of the effect of aspirin on human platelets. I. Acetylation of a particulate fraction protein. J Clin Invest . 1975; 56 624-632
16 Shimokawa T, Smith W L. Prostaglandin endoperoxide synthase. The aspirin acetylation region. J Biol Chem . 1992; 267 12387-12392
17 Picot D, Loll P J, Garavito R M. The X-ray crystal structure of the membrane protein prostaglandin H₂ synthase-1. Nature . 1994; 367 243-249
18 Matijevic-Aleksic N, Sanduja S K, Wang L-H. Differential expression of thromboxane A synthase and prostaglandin H synthase in megakaryocytic cell line. Biochim Biophys Acta . 1995; 1269 167-175
19 Kopp E, Ghosh S. Inhibition of NF-κB by sodium salicylate and aspirin. Science . 1994; 265 956-959
20 Schwenger P, Albert D, Skolnik E Y. Activation of P38 mitogen-activated protein kinase by sodium salicylate leads to inhibition of tumor necrosis factor-induced IκBα phosphorylation and degradation. Mol Cell Biol . 1998; 18 78-84
21 Yin M-J, Yamamoto Y, Gaynor R B. The anti-inflammatory agents aspirin and sodium salicylate inhibit the activity of IκB kinaseβ. Nature . 1998; 396 77-80
22 Grilli M, Pizzi M, Memo M. Neuroprotection by aspirin and sodium salicylate through blockade of NF-κB activation. Science . 1996; 274 1383-1385
23 Yuan M, Konstantopoulos N, Lee J. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of IKKβ. Science . 2001; 293 1673-1677
24 Hamberg M. Inhibition of prostaglandin synthesis in man. Biochem Biophys Res Commun . 1972; 49 720-726
25 Wu K K, Sanduja R, Tsai A-L. Aspirin inhibits interleukin-1-induced prostaglandin H synthase expression in cultured endothelial cells. Proc Natl Acad Sci USA . 1991; 88 2384-2387
26 Xu X-M, Sansores-Garcia L, Chen X-M. Suppression of inducible cyclooxygenase-2 gene transcription by aspirin and sodium salicylate. Proc Natl Acad Sci USA . 1999; 96 5292-5297
27 Saunders M A, Sansores-Garcia L, Gilroy D. Selective expression of C/EBPβ binding and COX-2 promoter activity by sodium salicylate in quiescent human fibroblasts. J Biol Chem . 2001; 276 18897-18904
28 Fletcher B S, Lim R W, Varnum B C. Structure and expression of TIS21, a primary response gene induced by growth factors and tumor promoters. J Biol Chem . 1991; 266 14511-14518
29 Tazawa R, Xu X-M, Wu K K. Characterization of the genomic structure, chromosomal location and promoter of human PGHS-2 gene. Biochem Biophys Res Commun . 1994; 203 190-199
30 Cianferoni A, Schroeder J T, Kim J. Selective inhibition of IL-4 gene expression in human T cells by aspirin. Blood . 2001; 97 1742-1749
31 Mitchell J A, Akarasereenont P, Thiemermann C. Selectivity of non-steroidal anti-inflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci USA . 1994; 90 11693-11697
32 Yamamoto Y, Yin M-J, Lin K-M. Sulindac inhibits activation of the NF-κB pathway. J Biol Chem . 1999; 274 27309-27314
33 Tegeder I, Niederberger E, Israr E. Inhibition of NF-κB and AP-1 activation by R- and S-flurbiprofen. FASEB J . 2001; 15 2-4
34 Shiff S J, Rigas B. The role of cyclooxygenase inhibition in the anti-neoplastic effects of non-steroidal anti-inflammatory drugs (NSAIDs). J Exp Med . 1999; 190 445-450