Inflammation is driven by complex metabolic pathways, with arachidonic acid (AA) as one important molecule of origin. AA metabolism is fundamental for both promotion and inhibition of inflammatory processes. Several enzymes are involved in this regulation of inflammation, cyclooxygenases 1 and 2 [
Early findings on aspirin inhibitory mode of action on prostaglandin (PG) synthesis led to the initial discovery of cyclooxygenase (COX) [
NSAIDs, by inhibiting cyclooxygenase enzyme activity, even by different means, may all share to a greater or lesser extent a similar kind of side effects [
Levels of possible side effects of NSAIDs [
Acetylation of serine (Ser-530) of COX-1 even by low aspirin concentrations and in a few minutes results in the inhibition of prostaglandin E2 (PGE2) formation and the inhibition of platelet function (anticoagulant activity) [
(a) Aspirin acetylation of COX-1 irreversibly inhibits arachidonic acid to become bound, whereas (b) acetylation of COX-2 leads to the formation of lipoxins [
The acetylation event by aspirin, shown to produce also the aspirin-triggered lipotoxins by transcellular (cell-to-cell) interactions [
The transcellular biosynthesis of lipoxins requires interactions between LOX isoenzymes (LOX-LOX interactions) and can promote generation of leukotrienes (LTs) by endothelial cells [
Metabolic events that follow acetylation of COX-2 and further transcellular activities: (a) eicosanoid production by crossover pathways of acetylated COX-2 and LOX isoenzymes [
5-S-HETE is on its own a potent proinflammatory mediator [
Free activated arachidonic acid not bound to COX-2 may be also used by 5-LOX to produce leukotrienes during inflammation in vivo [
The literature study was conducted from scientific journals and books and electronic sources such as SciFinder, Science Direct, Medline, and Google Scholar, covering the period from January 1945 to the end of December 2016.
Traditional NSAIDs during clinical practice vary on the degree of causing vascular side effects. Increased risk is noticed by high doses of diclofenac and ibuprofen due to the increased myocardial infarction events recorded, whereas increased doses of naproxen have substantially smaller risk [
In general, for traditional nonselective COX inhibitors, the mechanism of drug generated myocardial pathology [
The clear distinction between COX-1 and COX-2 inhibitors cannot be defined fully [
Withdrawal of rofecoxib (a similar agent to celecoxib with increased vascular side effects) from clinical use is perhaps the best example to account for side effects by a more selective COX-2 inhibitor [
Coadministration of aspirin in clinical practice is recommended for certain groups of patients taking vast amounts of NSAIDs as a thrombolytic agent for cardioprotection [
Eosinophils among other stimuli are also driven by LTC4, which is induced by NSAID use (Figures
As already described, NSAID side effects occur primarily due to the inhibition of cyclooxygenases that metabolize arachidonic acid and synthesize prostaglandins with beneficial activities under normal conditions [
Better chances to optimize treatment of NSAIDs with relatively high and low COX-2 inhibitory activities can perhaps be conferred by supplementary agents that may interfere with COX in a different manner.
Arachidonic acid hydrolyzed by cPLA2 (phospholipase A2), if not metabolized by cyclooxygenases, remains an available substrate to be used in other catabolic pathways: (1) the lipoxygenase, (2) the P450 epoxygenase, and (3) the nonenzymatic synthesis leading to isoprostane (Figure
It has been described that by inhibition of COX activity the increase of cysteinyl leukotriene family (CysLT) potent proinflammatory lipid mediators is feasible [
A way to circumvent proinflammatory leukotrienes (LTB4 and LTC4) production by an overwhelming 5-LOX activity may be the already developed specific LOX inhibitors [
NSAIDs activity as already discussed (Figures
Apart from LOX favored metabolism during COX inhibition, oxidized arachidonic acid may sustain nonenzymatic conversion to form prostaglandin F2 compounds (PGF2-isoprostanes). Isoprostanes are very readily formed in biological fluids [
Arachidonic acid, once liberated from membrane phospholipases and not being metabolized further by cyclooxygenases due to NSAID inhibition, may be efficiently metabolized by isoforms of the cytochrome P450 (CYP) family to form 20-hydroxyeicosatetraenoic acid (20-HETE) [
In order to identify agents that may inhibit undesired 20-HETE synthesis by NSAID-COX inhibition, the experimental model of spontaneous hypertensive rats provides significant clinical information. Agents that induce heme oxygenase reduce the renal formation of 20-HETE and also decrease hypertension [
Heme oxygenase-1 (HO-1), which is expressed in all tissues, receives electrons from NADPH by P450 enzyme fractions due to CRP microsomal protein mediator and P450 protein-to-protein interactions [
Another target for NSAID minimization of side effects on the cardiovascular system may be the maintenance of low levels of nitric oxide (NO) that are essential for cardioprotection [
Possible target points of supplementary agent’s use to alleviate NSAID promotion of proinflammatory and cancerous conditions.
Finally, recent scientific effort is focusing on the trials of new cyclooxygenase inhibitors [
Epidemiologic studies provide contradictory results on cancer risk development by NSAIDS that may be due to the cell-specific activity of producing prostanoids and the specificity on COX inhibition by a particular NSAID (Figures
Cancer risk development from NSAID use as recorded from various epidemiology studies.
Type of cancer | Aspirin | Traditional nonaspirin NSAID | More selective COX-2 inhibitor |
---|---|---|---|
Proximal |
No effect on risk [ |
Reduced risk [ |
No data available (NDA) |
|
|||
Distal |
Decreased risk [ |
Reduced risk [ |
NDA |
|
|||
|
Decreased risk [ |
No effect on risk [ |
NDA |
|
|||
Nonmelanoma skin cancer (NMSC) | Decreased risk for |
Decreased risk for BCC SCC [ |
Decreased risk for BCC SCC [ |
|
|||
Melanoma skin cancer (MSC) | Slightly decreased risk [ |
Slightly decreased risk [ |
No effect on risk [ |
|
|||
Breast ER/PR (+) | Highly increased risk by aspirin-only NSAID users [ |
No effect on risk by acetaminophen [ |
Increased risk [ |
|
|||
Breast ER/PR (−) | Highly increased risk by aspirin-only NSAID users [ |
No effect on risk by acetaminophen [ |
Increased risk [ |
|
|||
Brain glioma | No effect on risk [ |
No effect on risk [ |
No effect on risk [ |
|
|||
Brain meningioma | No effect on risk [ |
Slightly increased risk [ |
Slight increased risk [ |
|
|||
Hepatocellular Carcinoma (HCC) | Decreases risk [ |
Decreases risk [ |
Decreases risk [ |
|
|||
Intrahepatic cholangiosarcoma (ICC) | Decreases risk in men [ |
No effect on risk by ibuprofen [ |
No effect on risk [ |
|
|||
|
No effect on risk [ |
Increased risk with acetaminophen, even stronger for metastatic type [ |
Increased risk, even stronger for metastatic type [ |
|
|||
Esophageal squamous cell carcinoma (ESCC) | Decreased risk [ |
Slightly decreased risk [ |
Slightly decreased risk [ |
|
|||
Esophageal adenocarcinoma (EA) | Decreased risk [ |
Slightly decreased risk [ |
Slightly decreased risk [ |
|
|||
Noncardia gastric carcinoma | Decreased risk [ |
Slightly decreased risk [ |
Slightly decreased risk [ |
|
|||
Cardia gastric carcinoma | No effect on risk [ |
No effect on risk [ |
No effect on risk [ |
Subjects using certain types of NSAIDs are being protected from colorectal cancer [
Epidemiological studies are controversial regarding a protective [
Although epidemiology data on cancer risk by NSAIDs are controversial, by comparison of results important indications may be drawn (Table
Traditional and “more selective” COX inhibitors preferentially bind on arachidonic acid’s active site of respective isoenzymes. The degree to which COX inhibitors cause inhibition of COX-1, COX-2, or COX-3 depends on their selective preference for COX active sites [
PGE2 association with tumorigenesis has been thoroughly investigated. Measurement of increased amounts of PGE2 in colorectal cancer has long been implicated to contribute to tumorigenesis [
Frequent use of NSAIDS leading to depletion of COX activity may favor the metabolism of arachidonic acid by the LOX pathways [
Molecular pathways that may contribute to promoting cancer by NSAID use [
Proposed mechanism of heme oxygenase inducer application to overcome accumulation of toxic metabolites [
Furthermore, extensive 5-LOX activity from arachidonic acid accumulating from NSAID inhibition of COX may also lead to increased 5-OXO-ETE formation (Figures
Lipoxygenases are an emerging group of cancer targets as numerous studies indicate that 5-LOX and 15-LOX-1 are associated with the development of cancer via the NF-kB pathway [
Only scarce previous studies in the past have been focused on the avoidance of adverse effects of NSAID use [
It is hereby declared that all authors have no conflicts of interest.
A. M. Kyriakopoulos has written the manuscript with the assistance of M. Nagl. V. Zoumpourlis provided the unpublished cancer data. S. Baliou aided mostly with schematic presentations making her contribution adequate for coauthorship.
The authors thank N. Kotsalas MD and I. Panagiotopoulos, MD, for their aid with the schematic presentations and literature research. This manuscript has been solely supported by Nasco AD Biotechnology Laboratory. The authors also thank JPA Medical Co. for sponsorship of publication fees.