Sulindac, a non-steroidal anti-inflammatory drug, mediates breast cancer inhibition as an immune modulator.
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ABSTRACT:
SUBMITTER: Yin T
PROVIDER: S-EPMC4725989 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Alzheimer disease is the most severe neurodegenerative disease worldwide. In the past years, a plethora of small molecules interfering with amyloid-? (A?) aggregation has been reported. However, their mode of interaction with amyloid fibers is not understood. Non-steroidal anti-inflammatory drugs (NSAIDs) are known ?-secretase modulators; they influence A? populations. It has been suggested that NSAIDs are pleiotrophic and can interact with more than one pathomechanism. Here we present a magic angle spinning solid-state NMR study demonstrating that the NSAID sulindac sulfide interacts specifically with Alzheimer disease A? fibrils. We find that sulindac sulfide does not induce drastic architectural changes in the fibrillar structure but intercalates between the two ?-strands of the amyloid fibril and binds to hydrophobic cavities, which are found consistently in all analyzed structures. The characteristic Asp(23)-Lys(28) salt bridge is not affected upon interacting with sulindac sulfide. The primary binding site is located in the vicinity of residue Gly(33), a residue involved in Met(35) oxidation. The results presented here will assist the search for pharmacologically active molecules that can potentially be employed as lead structures to guide the design of small molecules for the treatment of Alzheimer disease.
| S-EPMC4661391 | biostudies-literature
Project description:Naproxen ((S)-6-methoxy-?-methyl-2-naphthaleneacetic acid) is a powerful non-selective non-steroidal anti-inflammatory drug that is extensively used as a prescription and over-the-counter medication. Naproxen exhibits gastrointestinal toxicity, but its cardiovascular toxicity may be reduced compared with other drugs in its class. Despite the fact that naproxen has been marketed for many years, the molecular basis of its interaction with cyclooxygenase (COX) enzymes is unknown. We performed a detailed study of naproxen-COX-2 interactions using site-directed mutagenesis, structure-activity analysis, and x-ray crystallography. The results indicate that each of the pendant groups of the naphthyl scaffold are essential for COX inhibition, and only minimal substitutions are tolerated. Mutation of Trp-387 to Phe significantly reduced inhibition by naproxen, a result that appears unique to this inhibitor. Substitution of S or CH(2) for the O atom of the p-methoxy group yielded analogs that were not affected by the W387F substitution and that exhibited increased COX-2 selectivity relative to naproxen. Crystallization and x-ray analysis yielded structures of COX-2 complexed to naproxen and its methylthio analog at 1.7 and 2.3 ? resolution, respectively. The combination of mutagenesis, structure analysis, and x-ray crystallography provided comprehensive information on the unique interactions responsible for naproxen binding to COX-2.
| S-EPMC2966109 | biostudies-literature
Project description:Aldo-keto reductase (AKR) 1C3 catalyzes the NADPH-dependent reduction of Delta(4)-androstene-3,17-dione to yield testosterone, reduction of estrone to yield 17beta-estradiol and reduction of progesterone to yield 20alpha-hydroxyprogesterone. In addition, it functions as a prostaglandin (PG) F synthase and reduces PGH(2) to PGF(2)alpha and PGD(2) to 11beta-PGF(2). Immunohistochemistry showed that AKR1C3 is over-expressed in invasive ductal carcinoma of the breast. Retroviral expression of AKR1C3 in MCF-7 breast carcinoma cells shows that each of the assigned reactions occur in a breast cell microenvironment. Steroid and prostaglandin conversions were monitored by radiochromatography. Prostaglandin conversion was validated by a second method using HPLC coupled to APCI-MRM/MS. The combined effect of the AKR1C3 catalyzed 17- and 20-ketosteroid reductions will be to increase the 17beta-estradiol:progesterone ratio in the breast. In addition, formation of PGF(2) epimers would activate F prostanoid receptors and deprive PPARgamma of its putative anti-proliferative PGJ(2) ligands. Thus, AKR1C3 is a source of proliferative signals and a potential therapeutic target for hormone-dependent and -independent breast cancer. Two strategies for AKR1C3 inhibition based on non-steroidal anti-inflammatory drugs were developed. The first strategy uses the Ullmann coupling reaction to generate N-phenylanthranilate derivatives that inhibit AKR1C enzymes without affecting PGH(2) synthase (PGHS) 1 or PGHS-2. The second strategy exploits the selective inhibition of AKR1C3 by indomethacin, which did not inhibit highly related AKR1C1 or AKR1C2. Using known structure-activity relationships for the inhibition of PGHS-1 and PGHS-2 by indole acetic acids we obtained N-(4-chlorobenzoyl)-melatonin as a specific AKR1C3 inhibitor (K(I)=6.0muM) that does not inhibit PGHS-1, PGHS-2, AKR1C1, or AKR1C2. Both strategies are informed by crystal structures of ternary AKR1C3.NADP(+).NSAID complexes. The identification of NSAID analogs as specific inhibitors of AKR1C3 will help validate its role in the proliferation of breast cancer cells.
| S-EPMC3076957 | biostudies-literature
Project description:BACKGROUND AND OBJECTIVES:Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with AKI. Their association with nephrotic syndrome has not been systematically studied. This study aimed to assess the risk of nephrotic syndrome associated with NSAID use. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:A matched case-control study was performed in the UK primary care database. Cases were patients with a first diagnosis of nephrotic syndrome and controls were those without nephrotic syndrome. NSAID exposure (grouped either based on cyclooxygenase enzyme selectivity and chemical groups) was classified as either current (use at the nephrotic syndrome diagnosis date and corresponding date in the control group), recent, or past use. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using unconditional logistic regression analysis. RESULTS:We included 2620 cases and 10,454 controls. Compared with non-use, current use of 15-28 days and >28 days of conventional NSAIDs was associated with a higher relative risk of nephrotic syndrome: adjusted OR, 1.34; 95% CI, 1.06 to 1.70, and OR, 1.42; 95% CI, 0.79 to 2.55, respectively. Also, recent use (discontinuation 1-2 months before nephrotic syndrome diagnosis date; OR, 1.55; 95% CI, 1.11 to 2.15) and past use (discontinuation 2 months-2 years; OR, 1.24; 95% CI, 1.07 to 1.43), but not current use of <15 days (OR, 0.78; 95% CI, 0.46 to 1.31) nor past use (discontinuation >2 years; OR, 0.96; 95% CI, 0.85 to 1.09) were associated with a higher relative risk of nephrotic syndrome as well as past use of selective COX-2 inhibitors (discontinuation 2-24 months; OR, 1.24; 95% CI, 0.98 to 1.58). Categorization based on chemical groups showed that acetic acid and propionic acid derivatives were associated with a higher risk of nephrotic syndrome. CONCLUSIONS:The use of conventional NSAIDs was associated with a higher risk of nephrotic syndrome starting from at least 2 weeks of exposure, as well as for recent and past exposure up to 2 years before the diagnosis of nephrotic syndrome. This higher risk appeared mainly attributable to acetic acid and propionic acid derivatives.
| S-EPMC6730525 | biostudies-literature
Project description:BackgroundNonsteroidal anti-inflammatory drugs (NSAIDs) are a family of COX1 and COX2 inhibitors used to reduce the synthesis of pro-inflammatory mediators. In addition, inflammation often leads to a harmful generation of nitric oxide. Efforts are being done in discovering safer NSAIDs molecules capable of inhibiting the synthesis of pro-inflammatory lipid mediators and nitric oxide to reduce the side effects associated with long term therapies.Methodology/principal findingsThe analogue of arachidonic acid (AA), 2-hydroxy-arachidonic acid (2OAA), was designed to inhibit the activities of COX1 and COX2 and it was predicted to have similar binding energies as AA for the catalytic sites of COX1 and COX2. The interaction of AA and 2OAA with COX1 and COX2 was investigated calculating the free energy of binding and the Fukui function. Toxicity was determined in mouse microglial BV-2 cells. COX1 and COX2 (PGH2 production) activities were measured in vitro. COX1 and COX2 expression in human macrophage-like U937 cells were carried out by Western blot, immunocytochemistry and RT-PCR analysis. NO production (Griess method) and iNOS (Western blot) were determined in mouse microglial BV-2 cells. The comparative efficacy of 2OAA, ibuprofen and cortisone in lowering TNF-? serum levels was determined in C57BL6/J mice challenged with LPS. We show that the presence of the -OH group reduces the likelihood of 2OAA being subjected to H* abstraction in COX, without altering significantly the free energy of binding. The 2OAA inhibited COX1 and COX2 activities and the expression of COX2 in human U937 derived macrophages challenged with LPS. In addition, 2OAA inhibited iNOS expression and the production of NO in BV-2 microglial cells. Finally, oral administration of 2OAA decreased the plasma TNF-? levels in vivo.Conclusion/significanceThese findings demonstrate the potential of 2OAA as a NSAID.
| S-EPMC3754997 | biostudies-literature
Project description:Many non-steroidal anti-inflammatory drugs (NSAIDs) (including sulphasalazine, sulindac, indomethacin, naproxen, salicylic acid, ibuprofen, piroxicam and mefenamic acid) were found to be competitive inhibitors (with respect to folate) of avian liver phosphoribosylaminoimidazolecarboxamide formyltransferase (AICAR transformylase, EC 2.1.2.3) and bovine liver dihydrofolate reductase (EC 1.5.1.3). In contrast, aspirin and the antipyretic-analgesic drugs acetaminophen and antipyrine were weak inhibitors of these enzymes. Structure-activity correlation suggests that an aromatic ring with a side chain containing a carboxylic acid is a requirement for competitive inhibition of the transformylase. The above-listed NSAIDs also inhibited the folate-coenzyme-mediated biosynthesis of serine from glycine and formate (i.e., the C1 index) by human blood mononuclear cells (BMCs) in experiments where the drug was added to a culture of BMCs. Acetaminophen had a weak inhibitory effect on the C1 index. Consistent with the results obtained in vitro is the observation that the C1 index of BMCs from rheumatoid-arthritis patients treated with drugs which possess little antifolate activity (e.g. acetaminophen) is higher than the C1 index of BMCs from rheumatoid-arthritis patients treated with NSAIDs possessing more potent antifolate activity (e.g. sulindac, sulphasalazine, naproxen and ibuprofen). The mean activity of the transformylase in BMCs taken from healthy humans was 1.98 nmol of product/h per 10(6) cells and the activity was positively correlated with BMC folate levels. These results are consistent with the hypothesis that (1) the antifolate activity of NSAIDs, and hence cytostatic consequences, are important factors in producing anti-inflammatory activity and (2) aspirin exerts its anti-inflammatory effects after its conversion into salicylic acid, which possesses greater antifolate activity than its parent compound.
| S-EPMC1130907 | biostudies-other
Project description:BackgroundNon-steroidal anti-inflammatory drug (NSAID) use is associated with decreased risk of some cancers. NSAID use modulates the epigenetic profile of normal colonic epithelium and may reduce risk of colon cancer through this pathway; however, the effect of NSAID use on the DNA methylation profile of other tissues including whole blood has not yet been examined.FindingsUsing the Sister Study cohort, we examined the association between NSAID usage and whole genome methylation patterns in blood DNA. Blood DNA methylation status across 27,589 CpG sites was evaluated for 871 women using the Illumina Infinium HumanMethylation27 Beadchip, and in a non-overlapping replication sample of 187 women at 485,512 CpG sites using the Infinium HumanMethylation450 Beadchip. We identified a number of CpG sites that were differentially methylated in regular, long-term users of NSAIDs in the discovery group, but none of these sites were statistically significant in our replication group.ConclusionsWe found no replicable methylation differences in blood related to NSAID usage. If NSAID use does effect blood DNA methylation patterns, differences are likely small.
| S-EPMC4578936 | biostudies-literature
Project description:The asymmetric unit of the title compound, sodium 2-[1-methyl-5-(4-methyl-benzo-yl)-1H-pyrrol-2-yl]acetate dihydrate, Na+·C15H14NO3 -·2H2O, contains two sodium cations, two organic anions (A and B) and two water mol-ecules. The coordination geometry around the sodium cations corresponds to a distorted octa-hedron. Each pair of sodium cations (A-A or B-B) is chelated by two bridging anions coordinated by the O atoms of the deprotonated carb-oxy-lic groups, and each sodium atom is coordinated by an O atom of a third anion, which connects pairs of sodium atoms, and a water mol-ecule. As a result, a two-dimensional polymer is formed in the crystal. Hirshfeld surface analysis and two-dimensional fingerprint plots were used to analyze the inter-molecular contacts present in the crystal.
| S-EPMC7869531 | biostudies-literature
Project description: Not available
| S-EPMC6733592 | biostudies-literature
Project description:Non-steroidal anti-inflammatory drugs (NSAIDs) are known to suppress the inflammatory response after surgery and are often used for pain control. This study aimed to investigate NSAID use after radical surgical resection for rectal cancer and long-term oncological outcomes. A cohort of patients who underwent anterior resection for rectal cancer between 2007 and 2013 in 15 hospitals in Sweden was investigated retrospectively. Data were obtained from the Swedish Colorectal Cancer Registry and medical records; follow-up was undertaken until July 2019. Patients who received NSAID treatment for at least 2 days after surgery were compared with controls who did not, and the primary outcome was recurrence-free survival. Cox regression modelling with confounder adjustment, propensity score matching, and an instrumental variables approach were used; missing data were handled by multiple imputation. The cohort included 1341 patients, 362 (27.0 per cent) of whom received NSAIDs after operation. In analyses using conventional regression and propensity score matching, there was no significant association between postoperative NSAID use and recurrence-free survival (adjusted hazard ratio (HR) 1.02, 0.79 to 1.33). The instrumental variables approach, including individual hospital as the instrumental variable and clinicopathological variables as co-variables, suggested a potential improvement in the NSAID group (HR 0.61, 0.38 to 0.99). conventional modelling did not demonstrate an association between postoperative NSAID use and recurrence-free survival in patients with rectal cancer, although an instrumental variables approach suggested a potential benefit.
| S-EPMC7893477 | biostudies-literature