Effects of non-steroidal anti-inflammatory drugs on polymorphonuclear leukocyte functions in vitro: focus on fenamates

Prostanoid-independent anti-rheumatic effects of non-steroidal anti-inflammatory drugs (NSAIDs) are a matter of debate. The aim of the present study was to compare the effects of chemically different NSAIDs (diclofenac, indomethacin, ketoprofen, paracetamol, piroxicam and four fenamates: flufenamic, meclofenamic, mefenamic and tolfenamic acids) on human polymorphonuclear leukocyte (PMN) functions, i.e. calcium ionophore A23187-triggered degranulation, leukotriene 134 (LTB4) release, platelet-activating factor (PAF) production and migration towards LTB4. The four fenamates caused a dose-dependent inhibition of each of the PMN functions tested. Flufenamic, meclofenamic and tolfenamic acids were about equipotent to inhibit PMN degranulation (IC₅₀s 21–32 M) and LTB4 release (IC₅₀s 21–25 M) whereas mefenamic acid achieved similar effects at somewhat higher drug concentrations. Tolfenamic and meclofenamic acids were the most potent fenamates to inhibit PAF synthesis (IC₅₀s 37 and 51 M) as well as migration towards LTB4 (IC₅₀s 61 and 92 M). Out of the other NSAIDs, diclofenac (which is chemically related to fenamates) suppressed degranulation as well as LTB4 and PAF production. Indomethacin inhibited LTB₄ and PAF synthesis whereas ketoprofen reduced degranulation. The inhibitory effects of the non-fenamate NSAIDs occurred only at drug concentrations far higher than those achieved clinically. Paracetamol and piroxicam (up to 300 M) did not influence the PMN functions tested. We conclude that NSAIDs with a fenamate structure differ from other NSAIDs by inhibiting PMN functions induced either by receptor-mediated stimulus (LTB4) or calcium ionophore (A23187) at micromolar drug concentrations. Correspondence to: E. Moilanen at the above address     

A comparison of the effect of timegadine, levamisole, and D-penicillamine on human neutrophil metabolism of endogenous arachidonic acid and chemotaxis

The effect of timegadine, a novel experimental antirheumatic drug, on human neutrophil (PMN) 5-lipoxygenase activity and leukotriene B4 (LTB4) chemotaxis was compared with that of two second-line antiinflammatory drugs, D-penicillamine and levamisole. 1-14C-Arachidonic acid (AA) was incorporated into the purified cells until steady state conditions were obtained. After preincubation with serial dilutions of the three drugs, AA release and metabolism was stimulated with calcium ionophore A23187. The radioactive eicosanoids released were extracted and separated by thin-layer chromatography, followed by autoradiography and quantitative laser densitometry. Chemotaxis of PMNs towards LTB4 was measured in a modified Boyden chamber. Timegadine showed dose-dependent inhibition of both the 5-lipoxygenase pathway (IC50 3.4 x 10(-5) M), and of chemotaxis (IC50 3 x 10(-4) M). Inhibition of the release of AA from phospholipids, however, occurred only at therapeutically irrelevant doses (millimolar concentrations). Levamisole and D-penicillamine did not inhibit any of the cell functions investigated. Inhibition of both neutrophil motility and cellular synthesis of pro-inflammatory eicosanoids, may thus contribute to the clinical effects of timegadine in rheumatoid arthritis.     

Orally administered tolfenamic acid inhibits leukotriene synthesis in isolated human peripheral polymorphonuclear leukocytes

Special interest has been focused on the development of dual inhibitors of the cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism. In contrast to other classic NSAIDs, some fenamates in clinically achievable concentrations have been shown to inhibit synthesis of 5-lipoxygenase products in vitro. In the present work, we studied the effect of orally administered tolfenamic acid (600 mg) on Ca ionophore A 23187 -induced leukotriene synthesis in isolated human polymorphonuclear leukocytes. Leukotriene production was reduced in all 14 subjects studied, the mean inhibition of LTB4 synthesis being 16 +/- 3% and that of LTC4 33 +/ 7%. The inhibition correlated positively with serum acid concentrations. We suggest that inhibition of leukotriene synthesis is an additional mechanism of the anti-inflammatory, antimigraine and antidysmenorrhoeic effects of tolfenamic acid, and a possible explanation for its rare gastric and bronchoconstrictive side-effects.     

Influence of Tolfenamic Acid on Airway Contractility in Guinea Pigs

Abstract The effect of the NSAIDs tolfenamic acid and indomethacin was tested on acetylcholine-induced and antigen-induced contractions in guinea pig airways. Indomethacin potentiated antigen-induced contractions while tolfenamic acid showed dilatory properties. The effect of the drugs on acetylcholine-induced contractions showed no significant differences; indomethacin had a slightly increasing tendency while tolfenamic acid reduced the contractile response. These results indicate that tolfenamic acid does not have bronchoconstrictive properties, which is a common side effect of other NSAIDs in asthmatics.     

Prostaglandin E2 inhibits and indomethacin and aspirin enhance, A23187-stimulated leukotriene B4 synthesis by rat peritoneal macrophages

1. The calcium ionophore, A23187, stimulated leukotriene B4 (LTB4), thromboxane B2 (TxB2) and prostaglandin E2 (PGE2) synthesis by 4 day carrageenin-elicited rat peritoneal macrophages. 2. At concentrations of 2 x 10(-7)-2 x 10(-5) M indomethacin and aspirin enhanced A23187-stimulated LTB4 synthesis and inhibited PGE2 and TXB2 formation. 3. PGE2 inhibited A23187-stimulated LTB4 and TXB2 formation as well as the augmentation of LTB4 release caused by aspirin and indomethacin. However, PGE2 was ineffective when the cells were challenged with arachidonic acid (AA). 4. Dibutyryl adenosine 3':5'-cyclic monophosphate (db-cyclic AMP) partially inhibited A23187-stimulated LTB4 production. 5. Our results suggest that PGE2 inhibits macrophage LTB4 synthesis by limiting the availability of AA. Indomethacin and aspirin, possibly by removing the regulatory effect of PGE2, promote the synthesis of the pro-inflammatory LTB4.     

Effect of a novel non-steroidal anti-inflammatory drug (M-5011) on cytokine levels in rats with monosodium urate crystal- induced pleurisy.

We evaluated the effects of a new non-steroidal anti-inflammatory drug (NSAID), d-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid (M-5011), and indomethacin on the production of arachidonate metabolites and pro-inflammatory cytokines in male Sprague-Dawley rats with monosodium urate crystal (MSU)-induced pleurisy. Levels of tumor necrosis factor (TNF), interleukin (IL)-1 and IL-6 in the pleural exudate were determined by biological assays, while prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and cytokine-induced chemoattractant-1 (CINC-1) levels were quantified by enzyme immunoassays. Orally administered M-5011 (5 mg/kg) decreased the pleural exudate volume at 3 and 4 hr after MSU injection. Indomethacin (10 mg/kg) decreased the volume at 3-5 hr. These drugs reduced the number of leukocytes in the pleural cavity at 6 hr. Both NSAIDs also reduced the content of PGE2 in the exudate without affecting LTB4 levels. Increased productions of both IL-6 and CINC-1 in the exudate were reduced by pretreatment with M-5011 or indomethacin, and TNF levels in the exudate were increased by pretreatment of these drugs. Thus, M-5011 inhibits the production of both IL-6 and CINC-1 at lower doses than those of indomethacin, and the inhibitory effect of M-5011 on CINC-1, but not IL-6, may partly contribute to the inhibition of leukocyte infiltration in rats with MSU-induced pleurisy.     

Comparison of the effects of some compounds on human neutrophil degranulation and leukotriene B4 and thromboxane B2 synthesis

The effects of aspirin, indomethacin, phenylbutazone, eicosatetraynoic acid (ETYA), nordihydroguaiaretic acid (NDGA) and 3-amino-1-[3-(trifluoromethyl)-phenyl]-2-pyrazoline (BW755C) on human neutrophil degranulation induced by A23187 and F-Met-Leu-Phe (FMLP) have been studied. These effects have been compared with those on A23187 induced leukotriene B4 (LTB4) and thromboxane B2 (TXB2) synthesis by these cells to elucidate the relationship between LTB4 formation and degranulation. All compounds inhibited TXB2 synthesis by 50% at concentrations between 0.0016 and 50 microM. The synthesis of LTB4 was inhibited by 50% by ETYA (1.9 microM) and by NDGA (0.52 microM). Degranulation induced by A23187 and FMLP was inhibited by 50% by ETYA (16 and 11 microM respectively) and by NDGA (1.5 and 6.5 microM respectively). In the case of ETYA the concentrations required to inhibit degranulation were significantly higher than those required to inhibit LTB4 synthesis. In contrast, BW755C inhibited LTB4 synthesis by 50% at 2.8 microM but did not affect A23187-induced degranulation and was only a weak inhibitor of FMLP-induced degranulation (50% inhibition at 89 microM). The effects of the above compounds on the omega-oxidation of LTB4 by human neutrophils has also been studied to investigate the mechanism of action of these compounds. None of the above compounds affected the metabolism of LTB4 by these cells suggesting that their actions are not as non-specific anti-oxidants. These data indicate that human neutrophil degranulation induced by FMLP and A23187 is independent of LTB4 synthesis.     

The relationship between diphenylamine structure and NSAIDs-induced hepatocytes injury

Objective

Many nonsteroidal anti-inflammatory drugs (NSAIDs) with diphenylamine structure induce severe hepatotoxicities. We evaluated the role of diphenylamine structure in liver injuries induced by these NSAIDs.

Methods

Effects of diphenylamine, diclofenac and tolfenamic acid on mitochondrial permeability transition (MPT) and efflux of calcium in isolated liver mitochondria as well as on cellular ATP content and mitochondrial membrane depolarization in rat primary hepatocyte cultures were examined.

Results

Diclofenac and tolfenamic acid induced cyclosporine A (CsA)-sensitive mitochondrial swelling and membrane depolarization in isolated liver mitochondria. Only diclofenac caused the release of calcium in isolated liver mitochondria. Diphenylamine had no effects on isolated liver mitochondria. All three compounds decreased ATP content and induced mitochondrial membrane depolarization. CsA attenuated these effects, suggesting MPT might be involved in the hepatotoxicities caused by diphenylamine, diclofenac and tolfenamic acid. SKF-525A, a general inhibitor of CYP450, markedly inhibited the injury induced by diphenylamine, but not diclofenac or tolfenamic acid.

Conclusion

The hepatotoxicities caused by diclofenac and tolfenamic acid may be attributed to the mitochondrial dysfunction induced by these drugs instead of the diphenylamine structure per se.     

Effects of long-term aurothiomalate and D-penicillamine treatments on renal function and urinary excretion of prostanoids in patients with rheumatoid arthritis

The effects of long-term aurothiomalate and D-penicillamine treatments on renal function and the urinary excretion of prostanoids were studied in 20 patients with classic or definite rheumatoid arthritis. Twelve-hour urine was collected overnight, on the following day blood samples were taken in the morning and 12-hour urine was collected during the following day. Albumin excretion into the urine was determined by a sensitive quantitative method. Beta-2-microglobulin (B2MIGLO) and N-acetyl-beta-glucosaminidase (NAG) serum concentrations and excretions into the urine were measured to detect possible tubular or glomerular damage, respectively. The excretions of prostaglandin E2 (PGE2), thromboxane B2 and 6-keto-PGF1 alpha into urine were determined. In the aurothiomalate group, albumin excretion ranged 1-16 mg/12 h, and in the penicillamine group 0.8-31 mg/12 h. In the penicillamine group, but not in the aurothiomalate group, total protein, B2MIGLO and PGE2 excretions were higher (p less than 0.05) during the daytime than during the night. The daytime excretion of PGE2 was higher (p less than 0.01) in the penicillamine than in the aurothiomalate group. In the penicillamine group B2MIGLO excretion into urine correlated (p less than 0.01) with PGE2 excretion in the daytime. According to the results, not even long-term aurothiomalate treatment affects renal prostanoid excretion, while penicillamine increases urinary PGE2 excretion. This could be related either to the cofactor-like activity of penicillamine in the prostanoid synthesis or to damage in tubular cells. The role of prostanoids in maintaining blood flow and filtration may be more important in patients with renal damage than in normal conditions.     

Delayed Hypersensitivity to Tuberculin in Rats: Effects of Antirheumatic Drugs

Abstract The effects of different antirheumatic drugs administered according to various dosing regimes on tuberculin hypersensitivity in rats have been assessed quantitating the changes of exudate volume and mononuclear cells immigration at the site of challenge. Dosing at the time of sensitization with aurothiomalate and D-penicillamine enhanced the cell immigration which was decreased by similar treatment with levamisole. Cyclophosphamide increased the exudate formation. Indomethacin had no effect. Dosing at the time of challenge caused a marked reduction of both the parameters by aurothiomalate and cyclophosphamide and enhancement by levamisole. D-penicillamine increased only the cellular immigration and indomethacin the exudate formation. Long treatment with aurothiomalate and cyclophosphamide suppressed the responses. Similar treatment with D-penicillamine and levamisole produced a significant enhancement. Indomethacin had no effect. The relevance of these findings to the testing and mode of action of antirheumatic drugs is discussed.     

Delayed hypersensitivity to tuberculin in rats: effects of antirheumatic drugs.

The effects of different antirheumatic drugs administered according to various dosing regimes on tuberculin hypersensitivity in rats have been assessed quantitating the changes of exudate volume and mononuclear cells immigration at the site of challenge. Dosing at the time of sensitization with aurothiomalate and D-penicillamine enhanced the cell immigration which was decreased by similar treatment with levamisole. Cyclophosphamide increased the exudate formation. Indomethacin had no effect. Dosing at the time of challenge caused a marked reduction of both the parameters by aurothiomalate and cyclophosphamide and enhancement by levamisole. D-penicillamine increased only the cellular immigration and indomethacin the exudate formation. Long treatment with aurothiomalate and cyclophosphamide suppressed the responses. Similar treatment with D-penicillamine and levamisole produced a significant enhancement. Indomethacin had no effect. The relevance of these findings to the testing and mode of action of antirheumatic drugs is discussed.     

Modulation of arachidonic acid metabolism by orally administered morniflumate in man.

Unlike other classic NSAIDs, some fenamates given at therapeutic concentrations, have been shown to inhibit, both in vitro and in vivo, the 5-lipoxygenase pathway of arachidonic acid cascade as well as the synthesis of cyclooxygenase products. This dual inhibitory property might represent an improvement in anti-inflammatory therapy. The aim of this work was to characterize the effect of morniflumate, administered at therapeutic dosages to normal human volunteers, on leukotriene B4 (LTB4) and thromboxane (TXB2) synthesis, both in purified PMNs and in whole blood. PMNs, isolated two hours after a single oral administration of morniflumate and at steady-state condition, fully retain their capacity to release LTB4 and TXB2. Since intracellular concentrations of the drug were undetectable, in spite of its elevated concentrations in platelet poor plasma, the results obtained using PMNs suggest a drug loss during the cells purification procedure. In whole blood experiments, morniflumate reduced blood LTB4 synthesis induced by Ca-ionophore A23187 Bx approximately 50%, both after single dose and at steady state; the degree of inhibition showed a pattern similar to the plasma levels of the bioactive metabolite of morniflumate (M1). The inhibition of serum TXB2 levels was higher than 85%. Hence, morniflumate is capable of reducing arachidonic acid metabolism acting both on cyclooxygenase and 5-lipoxygenase. This characteristic might provide a better approach in anti-inflammatory therapy.     

Effects of nonsteroidal anti-inflammatory drugs on rat gastric mucosal phosphodiesterase activity

In the present study, the effects of acetylsalicylic acid, diclofenac, ibuprofen, indomethacin, naproxen, phenylbutazone, proquazone, fluproquazone (RF 46-790 N), sulindac (sulfoxide and sulfide forms) and tolfenamic acid were compared on rat gastric mucosal cyclic nucleotide phosphodiesterases (PDEs). Some of the drugs inhibited PDEs effectively, the Ki values being clearly lower than those of theophylline. Mostly the type of inhibition was apparently competitive. Acetylsalicylic acid and ibuprofen were ineffective. No unambiguous correlation between the inhibition of mucosal PDEs and clinically observed gastric irritation was found. However, the inhibition of PDEs may modulate gastric side-effects of NSAIDs.     

Mechanisms underlying the anti-inflammatory activity and gastric safety of acemetacin

BACKGROUND AND PURPOSE: Acemetacin is regarded as a pro-drug of indomethacin and induces significantly less gastric damage but the reasons for this greater gastric safety of acemetacin are unclear. The anti-inflammatory effects of acemetacin have been attributed, at least in part, to its hepatic biotransformation to indomethacin. The aim of this study was to determine the effects of acemetacin and indomethacin in an in vivo model of acute inflammation and to examine the importance of biotransformation of acemetacin (to indomethacin) to its anti-inflammatory actions. EXPERIMENTAL APPROACH: The zymosan airpouch model was used in rats. Indomethacin or acemetacin (2.7-83.8 micromol kg(-1)) were administered orally or directly into the pouch. Leukocyte infiltration, prostaglandin (PG) E(2) and leukotriene (LT) B(4) levels in exudates, and whole blood thromboxane (TX) B(2) synthesis were measured. KEY RESULTS: Acemetacin was rapidly converted to indomethacin after its administration. Both acemetacin and indomethacin elicited comparable, dose-dependent reductions of leukocyte infiltration and of PGE(2) and TXB(2) synthesis. However, indomethacin induced more gastric damage than acemetacin and elevated LTB(4) production in the airpouch. CONCLUSIONS AND IMPLICATIONS: The similar effects of acemetacin and indomethacin on leukocyte infiltration and PG synthesis are consistent with rapid biotransformation of acemetacin to indomethacin. Some of this biotransformation may occur extra-hepatically, for instance in inflammatory exudates. Acemetacin probably exerts actions independent of conversion to indomethacin, given the different effects of these two drugs on LTB(4) production. Such differences may contribute to the relative gastric safety of acemetacin compared to indomethacin.     

Selective inhibition of arachidonate 5-lipoxygenase by novel acetohydroxamic acids: biochemical assessment in vitro and ex vivo

1. The chemically novel acetohydroxamic acids, BW A4C, BW A137C and BW A797C, are potent inhibitors of the synthesis of leukotriene B4 (LTB4) from arachidonic acid by human leucocyte homogenates: the concentrations required for 50% inhibition (IC50) were 0.1 microM, 0.8 microM and 0.5 microM respectively. Inhibition was less at higher concentrations of arachidonic acid. 2. These compounds also inhibited the synthesis of [14C]-5-HETE from [14C]-arachidonic acid and the calcium-dependent synthesis of LTB4 from 5-HPETE. This, therefore, suggests that they inhibit 5-lipoxygenase and LTA4 synthase. 3. Concentrations of acetohydroxamic acids required to inhibit metabolism of arachidonic acid by cyclo-oxygenase, 12-lipoxygenase and 15-lipoxygenase were 10 to 100 times higher than those required to inhibit 5-lipoxygenase. 4. The compounds were potent inhibitors of LTB4 synthesis induced by the ionophore, A23187, in human intact leucocytes. This inhibition was reversed by washing the cells. They were also potent, selective inhibitors of LTB4 synthesis induced by A23187 in whole rat blood: binding to rat plasma proteins did not greatly reduce the effectiveness of the compounds. 5. The effects of the acetohydroxamic acids, administered either intravenously or orally to rats, on the synthesis of LTB4, and thromboxane B2 (TXB2) in A23187-stimulated blood ex vivo was studied. The three compounds caused dose-dependent inhibition of the synthesis of LTB4 but not TXB2. Inhibition of LTB4 synthesis persisted for up to 6 h after a single oral dose of 50 mg kg-1. 6. The plasma concentrations of unchanged compound determined by h.p.l.c. correlated with the inhibition of LTB4 synthesis ex vivo.     

Auranofin stimulates LTA hydrolase and inhibits 5-lipoxygenase/LTA synthase activity of isolated human neutrophils

The effect of auranofin on the 5-lipoxygenase pathway was studied in human neutrophils stimulated with either fMLP or A23187 (with or without arachidonic acid). The synthesis of leukotriene B4 (LTB4), 5-HETE and the all-trans isomers of LTB4 was measured by HPLC. At low concentrations (0.5-2.0 microM), auranofin stimulated LTB4 synthesis, but inhibited it at higher concentrations (100% inhibition at less than 10 microM). In contrast auranofin caused dose-dependent inhibition of the synthesis of 5-HETE and the all-trans isomers of LTB4. Similar observations were made with each agonist. The stimulation of LTB4 synthesis and inhibition of the trans isomer production suggests that auranofin at low concentrations stimulates LTA hydrolase--the enzyme that converts LTA4 to LTB4, whereas the inhibition of synthesis of all lipoxygenase products at higher auranofin concentrations, suggests inhibition of 5-lipoxygenase/LTA synthase.     

Anti-inflammatory effect of FR140423, a novel selective cyclo-oxygenase-2 inhibitor, in rat adjuvant arthritis without gastrointestinal side effects

We investigated the effect of FR140423 (3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulphinyl)phen yl]pyrazole), a novel and selective cyclo-oxygenase (COX)-2 inhibitor, in rat adjuvant arthritis. The results were compared with that of indomethacin. We tested the inhibitory effects of FR140423 on paw oedema and the formation of the arachidonic acid metabolites prostaglandin (PG) E2 and leukotriene (LT) B4 in inflamed paws immunized with heat-killed and dried Mycobacterium tuberculosis. Oral administration of FR140423 showed a dose-dependent anti-inflammatory effect. This effect was two- to threefold more potent than that of indomethacin. The increase of PGE2 and LTB4 in inflamed paws was associated with the development of paw swelling. FR140423 and indomethacin dose-dependently suppressed the level of PGE2 but not LTB4 in arthritic paws. Unlike indomethacin, FR140423 did not induce gastric lesions even at doses up to 10 mgkg(-1) in arthritic rats. FR140423 has a potent anti-inflammatory effect mediated by inhibition of PGE2 produced by COX-2 in inflamed tissues. The safety profile of FR140423 appears to be an improvement on the safety profile of indomethacin.     

Effects of antirheumatic drugs on protein sulphydryl reactivity of human serum

The effect of a number of antirheumatic drugs on sulphydryl group reactivity in human serum has been determined using the thiol reagent, 5,5′-dithiobis (2-nitrobenzoic acid) (DTNB). Drug effects in vivo have been measured using sera from patients with rheumatoid arthritis receiving these compounds and the drugs have also been added to healthy human serum in vitro. An increased rate of sulphydryl-disulphide exchange between serum sulphydryl groups and DTNB was noted in rheumatoid disease. This finding was not associated with anti-inflammatory drug therapy. In vivo, non-steroidal anti-inflammatory drugs did not affect this reaction, but aurothiomalate, D-penicillamine and levamisole all significantly increased the rate of sulphydryl-disulphide exchange. When the drugs were added to healthy human serum in vitro, indomethacin, aurothiomalate and D-penicillamine stimulated sulphydryl reactivity with DTNB but levamisole had no effect. Aurothiomalate appeared to act in this system as a mixture of gold atoms and thiomalate molecules, the thiomalate stimulating and the gold inhibiting thiol reactivity. This study demonstrates that the stimulation of sulphydryl-disulphide exchange reactions in vivo is a property of three long-acting drugs used to treat rheumatoid arthritis, but not of non-steroidal antiinflammatory agents. This reactivity may therefore differentiate the second-line drugs showing true antirheumatic activity from ‘simple’ anti-inflammatory compounds. Comparative studies have shown that the addition of drugs to serum in vitro may give different results from those obtained with sera from rheumatoid patients receiving these agents. This may be due to in vivo metabolism of the compound, drug concentration effects or the parameters of the in vitro assay system. In view of this, caution is required in the interpretation of data obtained from in vitro studies of these compounds.     

白三烯B4在塞来昔布介导的抗癌效应中的作用

目的 研究白三烯B4(LTB4)在环氧合酶2(COX-2)抑制剂塞来昔布介导的抗癌效应中的作用.方法 MTT法检测塞来昔布、LTB4和去甲二氢愈创木酸(NDGA)对人结肠癌HT-29细胞和人前列腺癌PC-3细胞生存的影响以及LTB4对塞来昔布抗癌效应的影响.ELISA法检测塞来昔布对癌细胞中前列腺素E2(PGE2)和LTB4表达的影响.结果 塞来昔布抑制HT-29和PC-3细胞的生存及LTB4表达(P<0.05或P<0.01),但仅下调HT-29细胞的PGE2表达(P<0.01).LTB4能拮抗塞来昔布对HT-29细胞生长的抑制作用(P<0.01),NDGA明显抑制HT-29细胞的生存(P<0.01),而对PC-3细胞则没有这些作用.结论 塞来昔布对HT-29和PC-3细胞的抑制效应是COX-2非依赖性的,且只有在HT-29细胞中,塞来昔布的抗癌作用主要是通过下调LTB4实现的.     

Indomethacin decreases arachidonic acid uptake in HCA-7 human colon cancer cells

Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the incidence of colorectal cancer. However, evidence is accumulating that NSAIDs have anti-cancer effects in addition to inhibiting cyclooxygenase (COX)-mediated prostanoid biosynthesis. We now show that indomethacin, a popular NSAID, significantly reduced the [3H]-arachidonic acid uptake in HCA-7 human colon cancer cells. Interestingly, no decrease in the uptake of [3H]-arachidonic acid occurred when the cells were treated with aspirin, diclofenac, and sulindac even though the concentrations of these NSAIDs were high enough to inhibit COX-2 activity. These findings suggest that indomethacin has a novel anti-cancer effect that may be independent of COX-2 inhibition.