Open access peer-reviewed chapter

Mechanism of Action of Nonsteroidal Anti-Inflammatory Drugs

Written By

Newman Osafo, Christian Agyare, David Darko Obiri and Aaron Opoku Antwi

Submitted: 19 October 2016 Reviewed: 23 February 2017 Published: 23 August 2017

DOI: 10.5772/68090

From the Edited Volume

Nonsteroidal Anti-Inflammatory Drugs

Edited by Ali Gamal Ahmed Al-kaf

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The use of nonsteroidal anti-inflammatory drugs (NSAIDs) dates back to thousands of years when man used natural sources of these agents in a lot of pain and inflammatory conditions. The tone for modern day discovery and use of NSAIDs was set with the discovery of aspirin. Today in addition to aspirin, a host of other NSAIDs of varying potency and efficacy is employed in the management of pain and inflammatory conditions. This chapter looks with key interest in the existing and evolving role of NSAIDs in therapeutics with emphasis on the current insights into their mechanism of action and side effect profiles associated with its use in pain and inflammation as well as its potential therapeutic benefits in cancer chemotherapy.


  • nonsteroidal anti-inflammatory drugs
  • inflammation
  • cyclooxygenase
  • pain
  • fever

1. Introduction

The history of nonsteroidal anti-inflammatory drugs (NSAIDs) dates as far back as thousands of years with Hippocrates and other physicians prescribing the willow bark for a wide range of conditions [1]. The tone for the modern era of NSAIDs was, however, set by identifying salicin as the willow plant’s active ingredient and the subsequent introduction of acetylsalicylic acid by the Bayer Company about two centuries later [2]. Today in addition to aspirin, nonselective NSAIDs, such as piroxicam, mefenamic acid, diclofenac, naproxen, and selective cyclooxygenase-2 (COX-2) inhibiting NSAIDs, such as celecoxib and rofecoxib, remain mainstays of pain and inflammatory disorder therapy.

NSAIDs remain one of the most consumed drugs either by prescription or over-the-counter [3]. Their fever relieving effect has been well documented since their discovery and they have proven effective over the years in controlling pain and inflammatory conditions. It is particularly effective in acute and chronic orthopedic pain (osteoarthritis, ankylosing spondylitis, and rheumatoid arthritis) and postsurgical pain [4]. While these represent the traditional uses of NSAIDs, studies have pointed to their potential in Alzheimer’s [5], cancer [6], and Parkinson’s disease [7]. Most of these studies exploit the benefits of controlling the underlying inflammatory mechanisms of these diseases.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of therapeutic agents with diverse structural and pharmacodynamics profiles but similar mode of action. Broadly, NSAIDs are grouped into aspirin and nonaspirin NSAIDs. Despite similarities in their mechanism of action and toxicity profiles, they differ slightly in the manner they each interact with the cyclooxygenase enzyme [8]. A more popular classification, however, is based on structural differences and similarities [9]. They are grouped as follows: salicylates (aspirin), aryl alkanoic acids (diclofenac, indomethacin, nabumetone, sulindac), 2-arylpropionic acids or profens (ibuprofen, flurbiprofen, ketoprofen, and naproxen), n-arylanthranilic acids or fenamic acids (mefenamic acids, meclofenamic acid, pyrazolidine derivatives, e.g., phenylbutazone), oxicams (piroxicam, meloxicam), and sulfonamides (nimesulide).


2. Mechanism(s) of NSAIDs action

2.1. COX and COX inhibition

There is overwhelming evidence pointing to the inhibition of cyclooxygenase enzyme as the main mechanism of NSAIDs’ analgesic, antipyretic, and anti-inflammatory properties. Since the characterization of this mechanism by Vane for aspirin [10], other drugs in this class have proven consistent this mechanism. This is surprising considering the differences in structures of the individual drugs as described above. Cyclooxygenase (COX) inhibition and the resulting inhibition of prostaglandin and other eicosanoid synthesis mitigate pain, fever, and inflammation. The cyclooxygenase (COX) enzyme also known as prostaglandin endoperoxide H synthase (PGHS) exists in two isoforms: PGHS-1 or COX-1 and PGHS-2 or COX-2. There is a significant structural distinction between the two, with only 60% homology [11]. Although encoded by different genes, both isoforms are membrane-bound glycoproteins that catalyze the formation of prostanoid from arachidonic acid [12].

COX-1 is expressed constitutively in most mammalian cells and tissues such as seminal vesicle, platelets, and endothelium. In quiescent conditions, it performs ongoing regulatory functions referred to as “housekeeping duties.” Prostaglandins produced by COX-1 activity perform functions such as gastro and renal protection, macrophage differentiation, platelet aggregation, and mucus production [3, 13]. In inflammatory conditions, molecular studies have demonstrated that COX-1 mRNA and protein expression do not change, confirming their limited role in the inflammatory process [14]. COX-1, however, remains both experimentally and clinically relevant due to the adverse effects triggered by the nonselective inhibition of cyclooxygenase enzymes by some NSAIDs.

COX-2 is an inducible enzyme called upon by tissue injury and other stimuli such as lipopolysaccharide (LPS), interleukin-1, and tumor necrosis factor alpha (TNFα) [15, 16]. It is active at injury sites and in a variety of tissues such as the vascular endothelium, and rheumatoid synovial endothelial cells mediating inflammatory, pain, fever, and carcinogenic responses [17, 18]. A manifold increase in COX-2 levels occurs in inflammatory processes triggering an increased synthesis of pro-inflammatory prostaglandins. Initially thought of as exclusively inducible in nature, studies have shown COX-2 has some constitutive or regulatory roles. Housekeeping duties in reproduction, renal physiology, bone resorption, and neurotransmission have been documented [19, 20].

Indeed studies have shown that both isotypes are constitutive and inducible depending on the physiological conditions [21, 22]. COX-3, a third isotype, has been identified [23]. Its function, distribution, and role in NSAIDs mechanisms are still uncertain and subject of debate [24].

2.2. Pain, fever, and inflammation

The arachidonic acid pathway is central to inflammatory responses and consequently the mechanism of action of NSAIDs. Prostanoids, the end product of this pathway, performs a wide range of physiological functions.

NSAIDs are largely thought of as inhibitors of peripheral pain though several works in literature point to a potential and significant central analgesic activity. At the periphery, a host of mediators occurs to trigger nociception in response to physical, chemical, or electrical stimuli. Prostaglandins act synergistically with other mediators to sensitize nociceptors [10, 25]. Some NSAIDs have exhibited central analgesic effects in several animal models of pain. This is attributed to disruption of synthesis of central prostaglandins and other modulators in the nociceptive pathway. Arguments in favor of central activity stem from studies showing the inhibitory effect of NSAIDs on N-methyl-D-aspartate (NMDA) receptor activation-induced prostaglandin expression in cerebrospinal fluid [26] and antinociceptive effect of spinally administered ibuprofen [27] among others. A classic study by Hunskaar [28] showed overlapping time-effect relationship for aspirin and morphine in the first phase of formalin-induced pain response; a feature highly indicative of central activity.

NSAIDs have proven effective in inflammatory conditions such as arthritis, acute trauma, and pain associated with inflammation. Inflammatory mediators at injury site mediate vasodilation extravasation of protein exudates and nociception. Here, prostaglandins that are key players in this process are inhibited. Though COX inhibition is maintained as the main mechanism for the anti-inflammatory activity of NSAIDs, other mechanisms loosely referred to as non-COX mechanisms have been reported in the literature. NSAIDs are documented to have the suppressive effect in nuclear factor (NF)-κB, a transcription factor for pro-inflammatory proteins such as chemokines, adhesion molecules, and cytokines. NSAIDs also exhibit some suppression of activator protein 1, membrane stabilizing, and inhibition of reactive oxygen species (ROS) production [2931]. Although these are believed to contribute at a molecular level, it is unclear how they directly aid in the clinical benefits of NSAIDs.

NSAIDs relieve fever by inhibiting COX-mediated prostaglandin synthesis. Upon exposure to external pyrogens, mostly pathogen-associated molecular patterns (lipopolysaccharide, peptidoglycan, viral RNA, etc.), cells of the innate immune system respond by releasing endogenous pyrogens to induce pyrexia. Circulating interleukin-1, interleukin-6, and TNFα gets to the brain and induced the synthesis of prostaglandin via the cyclooxygenase in the preoptic hypothalamic region of the brain. Prostaglandin E2 (PGE2) binds to an EP-3 receptor of the endothelium of the hypothalamus to reset the body’s thermoregulation. An ensuing physiological process occurs to attain this set temperature. NSAIDs disrupt this process by COX inhibition and therefore have proven useful in curbing the harmful effects of high and persistent temperatures. It is important to note that they have no effect on normal body temperature or atypical rise in temperature such as malignant hyperthermia and heat stroke. Mechanisms in these cases are independent of the COX/prostaglandin inflammatory pathway.

2.3. Structure and mechanisms

Current studies have made it possible to understand the structural basis of both nonselective cyclooxygenase inhibition and COX-2 selective inhibition and the variations in individual NSAID’s interactions with COX. The catalytic site of COX-1 is long narrow hydrophobic channel spanning from the membrane-binding domain to the enzyme core. The threshold of the channel is made up of polar groups such as Arg120 and Glu524. NSAIDs bind at the upper portion of this channel specifically at a region near TYR385 and ARG120. Acidic NSAIDs, for instance, interact with ARG120 via hydrophobic and electrostatic forces [32].

While aspirin for instance irreversibly inhibits the COX enzyme by covalently modifying it active Ser529 [10], other NSAIDs such as ibuprofen and naproxen bind reversibly [33]. Studies by Kurumbail et al. [34] revealed a COX-2 3D structure closely resembling COX-1. An extra pocket in the COX-2 catalytic site, however, is created by the valine replacements at positions 523 and 434 (occupied by isoleucine in COX-1). This alteration in structure, among others, is exploited in the design of COX-2 selective drugs.

2.4. H2S-releasing derivatives of anti-inflammatory drugs

NSAIDs, including selective COX-2 inhibitors, are able to stimulate adherence of leukocytes to the vascular endothelium in the mesenteric circulations [3538] and that has been strongly associated with NSAID-induced gastric damage [3739]. With studies pointing to the ability of H2S donors to suppress leukocyte adherence, it would have been expected that an H2S-releasing NSAID would not induce leukocyte adherence and will be devoid of the gastric damaging property of NSAIDs. This is actually the case and was realized with studies conducted employing H2S-releasing derivative of diclofenac (ATB-337) on leukocyte adherence and gastric mucosal integrity in rat [40]. The diclofenac derivative did not stimulate leukocyte adherence and also not elevate lymphocyte function-associated antigen 1 (LFA-1) or intercellular adhesion molecule 1 (ICAM-1), as was observed in diclofenac; also, it did not cause gastric damage [41]. The H2S-releasing diclofenac, however, did not significantly inhibit gastric prostaglandin synthesis and systemic COX-1 activity [40]. Similar profile in activity was also observed in the H2S-releasing derivative of indomethacin (ATB-343).

H2S-releasing derivatives of NSAIDs have also been established to reduce infiltration of leukocytes in models of inflammation. A diclofenac derivative has been shown to reduce LPS-induced infiltration of neutrophils into the lung and liver [41]; also an H2S-releasing derivative of mesalamine profoundly reduced granulocyte infiltration in a mouse model of colitis [42] with effect significantly greater than that observed in the parent molecules in each case. H2S-releasing diclofenac was also realized to be more potent than diclofenac in reducing paw edema in the carrageenan-induced paw edema model in rat.

The upregulation in TNF-α and COX-2 expression in the rat stomach [43, 44] by NSAIDs is not observed in the H2S-releasing derivatives of NSAIDs despite their ability to cause marked suppression of gastric prostaglandin synthesis [40]. Moreover, these derivatives inhibit endotoxin-induced NF-κB activation and the associated increase in plasma TNF-α, nitrate, and nitrite [41].

2.5. Antitumor action of NSAIDs

NSAIDs have many effects that might contribute to chemoprevention of cancers such as colorectal cancer (CRC). This mode of prevention can be either COX-dependent or COX-independent which can be synergistic at different steps of this multistep process [45] with evidence for replacement of adenomatous polyposis coli (APC) function by NSAIDs. In this direction, sulindac and indomethacin have been shown to inhibit tumorigenesis through inhibition of peroxisome proliferator-activated receptor delta (PPARδ), a gene that is normally regulated by APC [46]. Currently, alterations of the COX-2-related pathways are in primary focus [47].

With NSAIDs being transcriptional inhibitors of COX-2 expression [48], these agents might selectively inhibit the induction of apoptosis in human intestinal stem cells with aberrant Wnt signaling [49]. The most compelling evidence of the possible chemopreventive action of some NSAIDs was the finding that aspirin reduces the risk of CRC in individuals with elevated COX-2 expression but not in those without [50] with associated reduced mortality [51], in an observational study. This was however experimentally confirmed when data affirmed the involvement of prostaglandins and nonprostaglandin COX-2 products were central to the development of CRC [52].

Measurable levels of NSAID-activated gene-1 (NAG-1) were detected in an NSAID-treated human CRC cell line. NAG-1 belongs to the transforming growth factor beta (TGFβ)-superfamily of growth factors and plays a significant role in apoptosis and tumorigenesis. In the CRC cells, NAG-1 expression positively correlates apoptosis and inversely correlates with COX-2 expression, with NAG-1 upregulation linked with NSAID administration in a Prostaglandin-independent manner [53]. Overexpression of NAG-1 in APC-mutated Min/+ mice results in reduced tumorigenesis. Interestingly, however, high COX-2 expression in colorectal tumors is associated with decreased expression of NAG-1, suggesting a reciprocal relationship [54]. It is henceforth being speculated that high levels of COX-2 in colorectal tumors suppress the expression of NAG-1; hence induction of NAG-1 by NSAIDs might contribute to the chemopreventive action of these agents [55].

Aspirin has a unique property of acetylating COX-2, which is not seen in other NSAIDs. This switches COX-2 from synthesizing prostaglandins (PGE2) (tumor promotion) to antitumorigenic 15-epi-lipoxin-A4 (LXA4), a 5-lipoxygenase catalyzed reaction. 15-epi-lipoxin-A4 is anti-inflammatory as well as anti-proliferative on carcinoma cells [56]. This effect of aspirin is seen at low antiplatelet doses with one study with 75 mg/day for 10 days not only reducing PGE2 formation and white cell accumulation in inflamed tissues but also significantly increasing local lipoxin production [57]. This establishes that the anticancer potential of aspirin may be due to lipoxin production.

Several studies also point to COX-2 independent actions may also play a role in apoptosis and such pathways have been realized to be sensitive to NSAIDs. Not all human CRCs express COX-2 and produce prostaglandins [58, 59]. However, the potency of NSAIDs to inhibit proliferation is similar to COX-2 producing CRC [60]. This is suggestive of the fact that the antitumor actions of NSAIDs are not necessarily via inhibition of COX-2 or prostaglandin formation [45, 59]. Sulindac reduces the number of aberrant crypt foci and adenomas in patients under conditions when etodolac, COX-2 inhibitor, was ineffective [61]. Moreover, sulindac was also found to significantly increase NAG-1 even in COX-2-deficient tumor cell lines [53].

The potential COX-2-independent mechanism of NSAIDs’ antineoplastic action includes downregulation of proto-oncogenes, such as c-myc, and transcriptional factors such as PPARδ, NF-κB, prostate apoptosis response-4 (PAR-4), and Bcl-2. The most recent therapeutic approach therefore entails combining NSAIDs and epidermal growth factor (EGF) receptor inhibitors in chemoprevention of CRC [62].


3. Conclusion

The therapeutic importance of NSAIDs in the management of acute and chronic pain and inflammation cannot be overemphasized. Also with the emergence of their therapeutic benefits in cancers, it is worth chronicling its pharmacological profile, specifically their established and expected mechanistic pathways of eliciting their activity. With promising outcomes in the experimental studies with improved gastrointestinal effects associated with modified NSAIDs and potential anticancer activity of NSAIDs, we strongly believe there is more to NSAIDs than we currently know. This chapter will henceforth give an insight into what is known and what could be possibly done in advancing the therapeutic potentials of NSAIDs beyond the management of pain and inflammation as we know.


  1. 1. Rao P, Knaus EE. Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): Cyclooxygenase (COX) inhibition and beyond. Journal of Pharmacy & Pharmaceutical Sciences. 2008;11(2):81-110
  2. 2. Vane JR. The fight against rheumatism: From willow bark to COX-1 sparing drugs. Journal of Physiology and Pharmacology. 2000;51:573-586
  3. 3. Bozimowski G. A review of nonsteroidal anti-inflammatory drugs. AANA Journal. 2015;83(6):425-433
  4. 4. KuKanich B, Bidgood T, Knesl O. Clinical pharmacology of nonsteroidal anti-inflammatory drugs in dogs. Veterinary Anaesthesia and Analgesia. 2012;39:69-90
  5. 5. Etminan M, Gill S, Samii A. Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer’s disease: Systematic review and meta-analysis of observational studies. British Medical Journal. 2003;327:128-132
  6. 6. Zhu JX, Song XQ, Lin HP, Young DC, Yan SQ, Marquez VE, Chen CS. Using cyclooxygenase-2 inhibitors as molecular platforms to develop a new class of apoptosis inducing agents. Journal of the National Cancer Institute. 2002;95:1745-1757
  7. 7. Teismann P, Tieu K, Choi DK, Wu DC, Naini A, Hunot S, Vila M, Jackson-Lewis V, Przedborski S. Cyclooxygenase-2 is instrumental in Parkinson’s disease neuro-degeneration. Proceedings of the National Academy of Sciences of the United States of America. 2003;100:5473-5478
  8. 8. Vonkeman HE, van de Laar MA. Nonsteroidal anti-inflammatory drugs: Adverse effects and their prevention. Seminars in Arthritis and Rheumatism. 2010;39:294-312
  9. 9. Meek IL, van de Laar MAFJ, Vonkeman HE. Non-steroidal anti-inflammatory drugs: An overview of cardiovascular risks. Pharmaceuticals (Basel). 2010;3(7):2146-2162
  10. 10. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature New Biology. 1971;231:232-235
  11. 11. Jones DA, Carlton DP, McIntyre TM, Zimmerman GA, Prescott SM. Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines. The Journal of Biological Chemistry. 1993;268:9049-9054
  12. 12. Liu J. Non-steroidal anti-inflammatory drugs and cancer, with an especial focus on esophageal cancer. Asian Pacific Journal of Cancer Prevention. 2011;12:3159-3168
  13. 13. Coleman RA, Smith WL, Narimiya S. Classification of prostanoid receptors: Properties, distribution and structure of the receptors and their subtypes. Pharmacological Reviews. 1994;46:205-229
  14. 14. Smith CJ, Zhang Y, Koboldt CM, Muhammad J, Zweifel BS, Shaffer A, Talley JJ, Masferrer JL, Seibert K, Isakson PC. Pharmacological analysis ofcyclooxygenase-1 in inflammation. Proceedings of the National Academy of Sciences of the United States of America. 1998;95:13313-13318
  15. 15. Masferrer JL, Isakson PC, Seibert K. Cyclooxygenase-2 inhibitors: A new class of anti-inflammatory agents that spare the gastrointestinal tract. Gastroenterology Clinics of North America. 1996;25:363-72
  16. 16. Meade EA, Smith WL, DeWitt DL. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. The Journal of Biological Chemistry. 1993;268:6610-6614
  17. 17. Atkinson TJ, Fudin J, Jahn HL, Kubotera N, Rennick AL, Rhorer M. What’s new in NSAID pharmacotherapy: Oral agents to injectables. Pain Medicine. 2013;14(1):11-17
  18. 18. Haeggström JZ, Rinaldo-Matthis A, Wheelock CE, Wetterholm A. Advances in eicosanoid research, novel therapeutic implications. Biochemical and Biophysical Research Communications. 2010;396(1):135-139
  19. 19. Breder CD, DeWitt DL, Kraig RP. Characterization of inducible cyclooxygenase in rat brain. Journal of Comparative Neurology. 1995;355:296-315
  20. 20. Pilbeam CC, Fall PM, Alander CB, Raisz LG. Differential effects of nonsteroidal antiinflammatory drugs on constitutive and inducible prostaglandin G/H synthase in cultured bone cells. Journal of Bone and Mineral Research. 1997;12:1198-1203
  21. 21. Wooten JG, Blikslager AT, Ryan KA, et al. Cyclooxygenase expression and prostanoid production in pyloric and duodenal mucosae in dogs after administration of nonsteroidal anti-inflammatory drugs. American Journal of Veterinary Research. 2008;69:457-464
  22. 22. Lascelles BD, King S, Roe S, et al. Expression and activity of COX-1 and 2 and 5-LOX in joint tissues from dogs with naturally occurring coxofemoral joint osteoarthritis. Journal of Orthopaedic Research. 2009;27:1204-1208
  23. 23. Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure and expression. Proceedings of the National Academy of Sciences. 2002;99:13926-13931
  24. 24. Kis B, Snipes JA, Busija DW. Acetaminophen and the cyclooxygenase-3 puzzle: Sorting out facts, fictions, and uncertainties. Journal of Pharmacology and Experimental Therapeutics . 2005;315:1-7
  25. 25. Ferreira SH, Moncada S, Vane JR. Indomethacin and aspirin abolish prostaglandin release from spleen. Nature. 1971; 231:237-9
  26. 26. Bjorkman R. Central antinociceptive effects of non-steroidal anti-inflammatory drugs and paracetamol. Acta Anaesthesiologica Scandinavica. 1995;39(103):1-44
  27. 27. Wang BC, Li D, Hiller J. The antinociceptive effect of S-(+) ibuprofenin rabbits: Epidural versus intravenous administration. Anesthesia & Analgesia . 1995;80:92-96
  28. 28. Hunskaar S. Similar effects of acetylsalicylic acid and morphine on immediate responses to acute noxious stimulation. Pharmacology & Toxicology. 1987;60:167-170
  29. 29. Tegeder I, Niederberger E, Israr E, Gühring H, Brune K, Euchenhofer C, Grösch S, Geisslinger G. Inhibition of NF-kappa B and AP-1 activation by R- and S-flurbiprofen. The FASEB Journal. 2001;15:595-597
  30. 30. Bryant CE, Farnfield BA, Janicke HJ. Evaluation of the ability of carprofen and flunixin meglumine to inhibit activation of nuclear factor kappa B. American Journal of Veterinary Research. 2003;64:211-215
  31. 31. Mounnissamy VM, Kavimani S, Balu V, Drlin QS. Evaluation of anti-inflammatory and membrane stabilizing properties of ethanol extract of Canjera rehedi. Iranian Journal of Pharmacology & Therapeutics. 2008;6:235-237
  32. 32. Mancini JA, Riendeau D, Falgueyret JP, Vickers PJ, O’Neill GP. Arginine 120 of prostaglandin G/H synthase-1 is required for the inhibition by nonsteroidal anti-inflammatory drugs containing a carboxylic acid moiety. The Journal of Biological Chemistry. 1995;270:29372-29377
  33. 33. Stanford N, Roth GJ, Shen TY, Majerus PW. Lack of covalent modification of prostaglandin synthetase (cyclo-oxygenase) by indomethacin. Prostaglandins. 1977;13:669-675
  34. 34. Kurumbail R, Stevens A, Gierse J, McDonald J, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, Isakson PC, Stallings WC. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature. 1996;384:644-648
  35. 35. Asako H, Kubes P, Wallace J, Gaginella T, Wolf RE, Granger DN. Indomethacin-induced leukocyte adhesion in mesenteric venules: Role of lipoxygenase products. American Journal of Physiology. 1992;262:G903-G908
  36. 36. Asako H, Kubes P, Wallace J, Wolf RE, Granger DN. Modulation of leukocyte adhesion to rat mesenteric venules by aspirin and salicylate. Gastroenterology. 1992;103(1):146-152
  37. 37. Wallace JL, McKnight W, Miyasaka M, Tamatani T, Paulson J, Anderson DC, Granger DN, Kubes P. Role of endothelial adhesion molecules in NSAID-induced gastric mucosal injury. American Journal of Physiology. 1993;265:G993-G998
  38. 38. Wallace JL, McKnight W, Reuter BK, Vergnolle N. NSAID-induced gastric damage in rats: Requirement for inhibition of both cyclooxygenase 1 and 2. Gastroenterology. 2000;119:706-714
  39. 39. Wallace JL, Arfors KE, McKnight GW. A monoclonal antibody against the CD18 leukocyte adhesion molecule prevents indomethacin-induced gastric damage in the rabbit. Gastroenterology. 1991;100:878-883
  40. 40. Wallace JL, Caliendo G, Santagada V, Cirino G, Fiorucci S. Gastrointestinal safety and anti-inflammatory effects of a hydrogen sulfide-releasing diclofenac derivative in the rat. Gastroenterology. 2007;132:261-271
  41. 41. Li L, Rossoni G, Sparatore A, Lee LC, Del Soldato P, Moore PK. Anti-inflammatory and gastrointestinal effects of a novel diclofenac derivative. Free Radical Biology and Medicine. 2007;42:706-719
  42. 42. Fiorucci S, Orlandi S, Mencarelli A, Caliendo G, Santagada V, Distrutti E, Santucci L, Cirino G, Wallace JL. Enhanced activity of a hydrogen sulphide-releasing derivative of mesalamine (ATB-429) in a mouse model of colitis. British Journal of Pharmacology. 2007;150:996-1002
  43. 43. Fiorucci S, Antonelli E, Distrutti E, Rizzo G, Mencarelli A, Orlandi S, Zanardo R, Renga B,Di Sante M, Morelli A, Cirino G, Wallace JL. Inhibition of hydrogen sulfide generation contributes to gastric injury caused by anti-inflammatory nonsteroidal drugs. Gastroenterology. 2005;129:1210-1224
  44. 44. Davies NM, Sharkey KA, Asfaha S, Macnaughton WK, Wallace JL. Aspirin induces a rapid up-regulation of cyclooxygenase-2 in the rat stomach. Alimentary Pharmacology & Therapeutics. 1977;11:1101-1108
  45. 45. Rigas B, Shiff SJ. Nonsteroidal anti-inflammatory drugs and the induction of apoptosis in colon cells: Evidence for PHS-dependent and PHS-independent mechanisms. Apoptosis. 1999;4(5):373-381
  46. 46. He TC, Chan TA, Vogelstein B, Kinzler KW. PPAR delta is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell. 1999;99(3):335-345
  47. 47. Wang D, Dubois RN. The role of COX-2 in intestinal inflammation and colorectal cancer. Oncogene. 2010;29(6):781-788
  48. 48. Wu KK. Salicylates and their spectrum of activities. Anti-Inflammatory, Anti-Allergy Agents in Medicinal Chemistry. 2007;6:278-292
  49. 49. Qiu W, Wang X, Leibowitz B, Liu H, Barker N, Okada H, et al. Chemoprevention by non-steroidal anti-inflammatory drugs eliminates oncogenic intestinal stem cells via SMAC-dependent apoptosis. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(46):20027-20032
  50. 50. Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. The New England Journal of Medicine. 2007;356(21):2131-2142
  51. 51. Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. Journal of the American Medical Association. 2009;302(6):649-658
  52. 52. Fischer SM, Hawk E, Lubet RA. Non-steroidal anti-inflammatory drugs and coxibs in chemoprevention: A commentary based primarily on animal studies. Cancer Prevention Research. 2011;4(11):1728-1735
  53. 53. Baek SJ, Kim KS, Nixon JB, Wilson LC, Eling TE. Cyclooxygenase inhibitors regulate the expression of a TGF-beta superfamily member that has proapoptotic and antitumorigenic activities. Molecular Pharmacology. 2001;59(4):901-908
  54. 54. Iguchi G, Chrysovergis K, Lee SH, Baek SJ, Langenbach R, Eling TE. A reciprocal relationship exists between non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) and cyclooxygenase-2. Cancer Letters. 2009;282(2):152-158
  55. 55. Schrör K. Pharmacology and cellular/molecular mechanisms of action of aspirin and non-aspirin NSAIDs in colorectal cancer. Best Practice & Research Clinical Gastroenterology. 2011;25:473-484
  56. 56. Claria J, Lee MH, Serhan CN. Aspirin-triggered lipoxins (15-epi-LX) are generated by the human lung adenocarcinoma cell line (A549)-neutrophil interactions and are potent inhibitors of cell proliferation. Molecular Medicine. 1996;2(5):583-596
  57. 57. Morris T, Stables M, Hobbs A, de Souza P, Colville-Nash P, Warner T, et al. Effects of low-dose aspirin on acute inflammatory responses in humans. The Journal of Immunology. 2009;183(3):2089-2096
  58. 58. Marnett LJ. Aspirin and the potential role of prostaglandins in colon cancer. Cancer Research. 1992;52(20):5575-5589
  59. 59. Hanif R, Pittas A, Feng Y, Koutsos MI, Qiao L, Staiano-Coico L, Shiff SI, Rigas B. Effects of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway. Biochemical Pharmacology. 1996;52(2):237-245
  60. 60. Dihlmann S, Siermann A, von Knebel Doeberitz M. The nonsteroidal anti-inflammatory drugs aspirin and indomethacin attenuate beta-catenin/TCF-4 signaling. Oncogene. 2001;20(5):645-653
  61. 61. Takayama T, Nagashima H, Maeda M, Nojiri S, Hirayama M, Nakano Y, et al. Randomized double-blind trial of sulindac and etodolac to eradicate aberrant crypt foci and to prevent sporadic colorectal polyps. Clinical Cancer Research. 2011;17(11):3803-3811
  62. 62. Torrance CJ, Jackson PE, Montgomery E, Kinzler KW, Vogelstein B, Wissner A, Nunes M,Frost P, Discafani CM. Combinatorial chemoprevention of intestinal neoplasia. Nature Medicine. 2000;6:1024-1028

Written By

Newman Osafo, Christian Agyare, David Darko Obiri and Aaron Opoku Antwi

Submitted: 19 October 2016 Reviewed: 23 February 2017 Published: 23 August 2017