Table 3: NSAIDs induced ROS generation in different cell types.
(a)

NSAIDs
Nonselective/semiselective
Sources of ROS generationCells/models/animals studiedOutcomesReferences

Diclofenac, indomethacin, ketoprofenMitochondrial respirationSaccharomyces cerevisiae Yeast cells BY4741 and mitochondrial DNA deletion (rho0) strainsThese NSAIDs target mitochondria to induce cell toxicity [95]
Ibuprofen and naproxenThese NSAIDS induce toxicity independent of mitochondrial respiration[95]

Indomethacin, sodium diclofenac, flurbiprofen, zaltoprofen, and mofezolacNDHuman gastric epithelial cell line AGSAll NSAIDs except mofezolac increased apoptotic DNA fragmentation and expression of COX-2 mRNA. DNA fragmentation induced by indomethacin or flurbiprofen was reduced by antioxidants. Indomethacin at 1 mM was a potent inducer of ROS generation in the cells[79]

Diclofenac and naproxen NADPH oxidasesSpontaneous hypertensive ratsNADPH oxidase expression increased in the heart and aorta by diclofenac and naproxen. ROS levels increased due to NADPH oxidase[114]
Human EA.hy 926
Endothelial cells
Nox2 isoform of NADPH oxidase is increased by diclofenac[114]

Aspirin, naproxen, and piroxicamNADPH oxidasesRat adipocytesActivation of NOX 4 isoform of NADPH oxidase results in the generation of H2O2[115]

IndomethacinXanthine oxidasesHuman colonic adenocarcinoma cells (Caco-2 cells)Xanthine oxidase activity increases by more than 100% 1 hour after treatment[96]

IndomethacinMitochondria superoxide leakageRat gastric epithelial cell line RGM1 Indomethacin induced the leakage of superoxide anion in the isolated mitochondria from the gastric RGM1 cells[93]

Indomethacin, diclofenac sodium, and aspirinNDRat gastric epithelial cell line RGM1 and rat small intestinal epithelial cell line IEC6Indomethacin, diclofenac, and aspirin in gastric RGM1 cells and small intestinal IEC6 cells increased lipid peroxidation[93]

Sulindac, sulindac sulfide, and sulindac sulfone NDPancreas carcinoma BXPC3, glioblastoma A172, colon carcinoma DLD-1, oral squamous SAS, and acute myelocytic leukemia HL60 cellsThe NSAID sulindac and its metabolites sulindac sulfide and sulindac sulfone all increased ROS generation. Sulindac sulfide showed the greatest ROS generation[80]

Indomethacin, piroxicam, and aspirinLipoxygenasesGastric and intestinal mucosa in miceResults in an overproduction of leukotrienes and products of 5-lipoxygenase activity. Increases in leukotriene and 5-lipoxygenase activity have been associated with ROS generation[123, 124, 127]

IndomethacinLipoxygenasesEfferent gastric circulation of pigsTime dependent formation of leukotriene-C4[128]

DiclofenacCytochrome P450 enzymesSaccharomyces cerevisiae yeast cells expressing the mutant P 450 BM3 M11 (capable of metabolizing diclofenac similar to humans)Increased ROS production by ~1.5 and 1.8 times at concentrations of 30 μM and 50 μM, respectively, compared to wild type[140]

Diclofenac, indomethacin, ketoprofen, and naproxenCytochrome P450 enzymesSaccharomyces cerevisiae Yeast cells BY4741 and mitochondrial DNA deletion (rho0) strainsNSAIDs metabolism associated with increased P450-related toxicity[95]

(b)

NSAIDs
coxibs
Sources of ROS generationCells/models/animals studiedOutcomesReferences

Ibuprofen, ketoprofen, and indomethacinCytochrome P450 enzymesBacillus megaterium All the NSAIDs caused a marked increase in the total cytochrome P450 level[142]

Aspirin, diclofenac, diflunisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, mefenamic acid, naproxen, piroxicam, sulindac, and tolmetinCytochrome P450 enzymesRat hepatocytesCytotoxicity of diclofenac, ketoprofen, and piroxicam was increased by cytochrome P450 causing hepatotoxicity[138]

Diclofenac and naproxenEndothelial nitric oxide synthaseSpontaneous hypertensive ratsIncreased expression of eNOS mRNA due to the generation of H2O2 which is responsible for upregulation of eNOS at the transcriptional and post-transcriptional levels[114]

Rofecoxib and celecoxibNADPH oxidasesSpontaneous hypertensive ratsNADPH expression increased in the heart and aorta by rofecoxib and celecoxib[114]
Human EA.hy 926
Endothelial cells
Nox2 Expression increased by rofecoxib [114]

Rofecoxib and celecoxibEndothelial nitric oxide synthaseSpontaneous hypertensive ratsIn the aorta, the coxibs did not show any eNOS mRNA expression. In the heart only rofecoxib showed a significant increase in the expression of eNOS[114]

EtodolacNDHuman gastric epithelial cell line AGSIncreased apoptotic DNA fragmentation and expression of COX-2 mRNA [79]

NimesulideNADPH oxidasesRat adipocytesActivation of NOX 4 isoform of NADPH oxidase results in the generation of H2O2[115]

*Although other reports are available suggesting the role of NSAIDs in ROS formation, the table lists only those NSAIDs for which results show that these NSAIDs are associated with CVD or NSAIDs mentioned in the text.