Nitric Oxide-donating Nonsteroidal Anti-inflammatory Drugs Research Articles

Correction to "Nitric Oxide-Donating Nonsteroidal Anti-Inflammatory Drugs Inhibit the Growth of Various Cultured Human Cancer Cells: Evidence of a Tissue Type-Independent Effect".

Correction to "Nitric Oxide-Donating Nonsteroidal Anti-Inflammatory Drugs Inhibit the Growth of Various Cultured Human Cancer Cells: Evidence of a Tissue Type-Independent Effect".

Nitric oxide-releasing indomethacin enhances susceptibility to Trypanosoma cruzi infection acting in the cell invasion and oxidative stress associated with anemia

Trypanosoma cruzi is the causative agent of Chagas disease. Approximately 8 million people are thought to be affected with this disease worldwide. T. cruzi infection causes an intense inflammatory response, which is critical for the control of parasite proliferation and disease development. Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) are an emergent class of pharmaceutical derivatives with promising utility as chemopreventive agents. In this study, we investigated the effect of NO-indomethacin on parasite burden, cell invasion, and oxidative stress in erythrocytes during the acute phase of infection. NO-indomethacin was dissolved in dimethyl formamide followed by i.p. administration of 50ppm into mice 30min after infection with 5×103 blood trypomastigote forms (Y strain). The drug was administered every day until the animals died. Control animals received 100μL of drug vehicle via the same route. Within the NO-indomethacin-treatment group, parasitemia and mortality (100%) were higher and oxidative stress in erythrocytes, anemia, and entry of parasites into macrophages were significantly greater than that seen in controls. Increase in the entry and survival of intracellular T. cruzi was associated with inhibition of nitric oxide production by macrophages treated with NO-indomethacin (2.5μM). The results of this study provide strong evidence that NO-NSAIDs potently inhibit nitric oxide production, suggesting that NO-NSAID-based therapies against infections would be difficult to design and would require caution.

The effects of aspirin, flurbiprofen, and NO-donating acetylsalicylic acid(NCX 4016) on mice models of endotoxic and septic shock

Nitric oxide-donating nonsteroidal antiinflammatory drugs (NO-NSAIDs) are a promising new class of antiinflammatory agents, which are obtained by adding NO-donating moieties to the existing conventional NSAID molecules. The aim of this study was to investigate the effects of aspirin, flurbiprofen, and NO-donating acetylsalicylic acid (NCX 4016) on cecal ligation and puncture (CLP) and endotoxin-induced septic shock (LPS) models in mice. Overall survival and spleen and liver weights were monitored in LPS and CLP models. Histopathological examinations of liver and spleen were performed at the end of the experimental protocols. NCX 4016 was able to reverse the increased spleen weight in CLP-operated animals, whereas aspirin or flurbiprofen did not. Similar to the results of the CLP model, none of the drugs modified the survival rates in the LPS model. Flurbiprofen in particular produced significant histopathological damage in spleens and livers, which was less significant with aspirin. NCX 4016 did not cause any liver damage. NCX 4016 has the potential to be used in septic states, while special attention has to be paid to the effects of aspirin and flurbiprofen on the liver and spleen.

NO‐sulindac inhibits the hypoxia response of PC‐3 prostate cancer cells via the Akt signalling pathway

Nitric oxide-donating non-steroidal anti-inflammatory drugs are safer than traditional NSAIDs and inhibit the growth of prostate cancer cells with greater potency than NSAIDs. In vivo, prostate cancer deposits are found in a hypoxic environment which induces resistance to chemotherapy. The aim of this study was to assess the effects and mechanism of action of a NO-NSAID called NO-sulindac on the PC-3 prostate cancer cell line under hypoxic conditions. NO-sulindac was found to have pro-apoptotic, cytotoxic, and anti-invasive effect on PC-3 cells under normoxia and hypoxia. NO-sulindac was significantly more cytotoxic than sulindac at all oxygen levels. The sulindac/linker and NO-releasing subunits both contributed to the cytotoxic effects of NO-sulindac. Resistance of PC-3 cells to NO-sulindac was induced as the oxygen concentration declined. Hypoxia-induced chemoresistance was reversed by knocking-down hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA using RNAi. Nuclear HIF-1alpha levels were upregulated at 0.2% oxygen but reduced by treatment with NO-sulindac, as was Akt phosphorylation. NO-sulindac treatment of hypoxic PC-3 cells transfected with a reporter construct, downregulated activation of the hypoxia response element (HRE) promoter. Co-transfection of PC-3 cells with the HRE promoter reporter construct and myr-Akt (constitutively active Akt) plasmids reversed the NO-sulindac induced reduction in HRE activation. Real-time polymerase chain reaction analysis of hypoxic, NO-sulindac treated PC-3 cells showed downregulation of lysyl oxidase and carbonic anhydrase IX mRNA expression. Collectively, these novel findings demonstrate that NO-sulindac directly inhibits the hypoxia response of PC-3 prostate cancer cells by inhibiting HIF-1alpha translation via the Akt signalling pathway. The ability of NO-sulindac to inhibit tumour adaption to hypoxia has considerable relevance to the future management of prostate cancer with the same cellular properties as PC-3.

THE POTENTIAL ROLE OF NITRIC OXIDE DONATING NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NO-NSAIDs) AS NEOADJUVENT THERAPY PRIOR TO IRRADIATION OF HYPOXIC PROSTATE CANCER CELLS

You have accessJournal of Urology1 Apr 2008THE POTENTIAL ROLE OF NITRIC OXIDE DONATING NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NO-NSAIDs) AS NEOADJUVENT THERAPY PRIOR TO IRRADIATION OF HYPOXIC PROSTATE CANCER CELLS Grant D Stewart, Jyoti Nanda, Jill G Christie, David JG Brown, Antony CP Riddick, James A Ross, and Fouad K Habib Grant D StewartGrant D Stewart More articles by this author , Jyoti NandaJyoti Nanda More articles by this author , Jill G ChristieJill G Christie More articles by this author , David JG BrownDavid JG Brown More articles by this author , Antony CP RiddickAntony CP Riddick More articles by this author , James A RossJames A Ross More articles by this author , and Fouad K HabibFouad K Habib More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(08)60130-5AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "THE POTENTIAL ROLE OF NITRIC OXIDE DONATING NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NO-NSAIDs) AS NEOADJUVENT THERAPY PRIOR TO IRRADIATION OF HYPOXIC PROSTATE CANCER CELLS." The Journal of Urology, 179(4S), p. 43 © 2008 by American Urological AssociationFiguresReferencesRelatedDetails Volume 179Issue 4SApril 2008Page: 43 Advertisement Copyright & Permissions© 2008 by American Urological AssociationMetricsAuthor Information Grant D Stewart More articles by this author Jyoti Nanda More articles by this author Jill G Christie More articles by this author David JG Brown More articles by this author Antony CP Riddick More articles by this author James A Ross More articles by this author Fouad K Habib More articles by this author Expand All Advertisement PDF DownloadLoading ...

Development of novel agents based on nitric oxide for the control of colon cancer

Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) represent a novel class of compounds that hold promise as agents for the control of colon cancer. They are derivatives of conventional NSAIDs that have been modified by adding to them, via a spacer molecule, a nitric oxide releasing moiety. The expectation is that the combined effects of NO and the NSAID moiety will exceed those of each structural component alone. Extensive work has demonstrated their potency and efficacy in preclinical models of colon cancer. The mechanism of action of NO-NSAIDs involves the modulation of several critical cellular signaling pathways, whereas the induction of a state of oxidative stress, at least by NO-aspirin, appears to be a major proximal event. Clinical trials are needed to assess the role of NO-NSAIDs in the control of colon cancer.

The use of nitric oxide-donating nonsteroidal anti-inflammatory drugs in the chemoprevention of colorectal neoplasia

Nitric oxide-donating nonsteroidal anti-inflammatory drugs are emerging as a promising class of compounds for the chemoprevention of colon cancer. Recent progress in their preclinical and mechanistic evaluation is reviewed. Compared to their parent compounds, nitric oxide-donating nonsteroidal anti-inflammatory drugs are up to several hundred times more potent in inhibiting the growth of colon cancer cell lines and also quite effective in preventing colon cancer in various tumor animal models. Their chemopreventive effect is brought about through a strong cell kinetic effect, including inhibition of proliferation, induction of cell death and inhibition of cell cycle phase transitions. The induction of oxidative stress appears mechanistically crucial. Pleiotropic effects on cell signaling have been identified including Wnt, NOS2, mitogen-activated protein kinase and Nrf2 signaling. Nitric oxide-donating nonsteroidal anti-inflammatory drugs, particularly nitric oxide-donating aspirin, appear to be very safe compounds, as evidenced from many animal and early human studies. Nitric oxide-donating nonsteroidal anti-inflammatory drugs hold the promise of being safe and effective chemopreventive agents against colon cancer. Clinical trials are needed to determine whether these drugs can be applied clinically.

Molecular characterization of cytotoxic and resistance mechanisms induced by NCX 4040, a novel NO-NSAID, in pancreatic cancer cell lines*

Although non steroidal antiinflammatory drugs (NSAIDs) have been shown to be effective as chemopreventive agents, important side-effects limit their clinical use. A promising novel class of drugs, nitric oxide-donating NSAIDs (NO-NSAIDs), has been found to be more active than classical NSAIDs. This study explored the effect of the NO-donating aspirin derivative, NCX 4040, on three human pancreatic adenocarcinoma cell lines (Capan-2, MIA PaCa-2 and T3M4). NCX 4040 activity was compared with that of NCX 4016 (an NO(2)-positional isomer of NCX 4040), SNAP (a standard NO-releasing molecule), NCX 4042 (denitrated analog of NCX 4040), and aspirin. NCX 4040 showed a striking cytocidal activity in all cell lines, already inducing significant percentages of apoptotic cells at 10 muM in Capan-2 cell lines. This study focused on the biological mechanisms of sensitivity and resistance to NCX 4040, highlighting that the cytotoxic action of this drug may be due to the hyperexpression of Bax, its translocation to the mitochondria, the release of Cytochrome C, and the activation of caspases-9 and -3, overall in a p53-independent manner. Moreover, the use of a specific COX-2 inhibitor (NS 398) in the experimental models showed that COX-2 hyperexpression could partially explain the resistance mechanisms to NCX 4040.

INFLUENCE OF NITRIC OXIDE-DONATING NONSTEROIDAL ANTI-INFLAMMATORY DRUGS ON THE EVOLUTION OF ACUTE PANCREATITIS

Microcirculatory disturbances and leukocyte activation are main events in the pathogenesis of acute pancreatitis (AP) that is characterized by inflammatory up-regulation. Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) regulate vascular function and mitigate inflammation. To investigate the influence of NO-NSAIDs on AP. AP was induced by the biliopancreatic duct outlet exclusion-closed duodenal loops model. Treatment with NO-flurbiprofen, NO-ibuprofen, NO-aspirin, or their parental drugs was done (i) 1 h before, (ii) 1 h after, (iii) 1 h before and 4 h after, or (iv) 4 h after surgery. The degree of severity was evaluated using biochemical and histopathological analyses. NO-NSAIDs given before and during the first hour of the noxia decreased blood levels of amylase, lipase, C-reactive protein, IL-6, IL-10, heat shock protein 72, prostaglandin E2 inactive metabolite, and 8-isoprostane, as well as pancreatic and lung myeloperoxidase and cyclooxygenase. Acinar and fat necrosis, hemorrhage, and leukocyte infiltrate were also reduced. The best protection was achieved when treatment was performed 1 h before and 4 h after triggering AP. NO-flurbiprofen was the most effective drug. AP severity was significantly ameliorated by NO-NSAIDs being the administration time essential to achieve optimal pancreatic protection that may result to be useful in the prevention of postendoscopic severe AP.

234 Induction of cell death by imidazoacridinone derivative C-1311 in T lymphoblastoid leukemia MOLT4 cells

Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) consist of a conventional NSAID to which an NO-releasing moiety is attached covalently, often via a spacer molecule. NO-NSAIDs represent an emerging class of compounds with chemopreventive properties against a variety of cancers, demonstrated in preclinical models including cell culture systems and animal tumor models; their potential efficacy in humans has not been assessed. Their mechanism of action appears complex and involves the generation of reactive oxygen species, suppression of microsatellite instability in mismatch repair-deficient cells, and modulation of several signaling cascades that culminate in inhibited cell renewal and enhanced apoptosis. NO, long appreciated to be able to protect from and also promote cancer, is released form NO-NSAIDs and constitutes their defining property. Existing data are consistent with the notion that NO may mediate their anticancer effect. In addition there is evidence that long-term administration of NO-donating compounds is not associated with increased incidence of colon cancer. Whether NO release is required for the anticancer effect of NO-NSAIDs has being questioned by recent data indicating that, at least in the case of NO-aspirin, the NO-releasing moiety may serve as a leaving group while the spacer actually being the moiety responsible for its pharmacological action. Regardless of mechanistic issues, these compounds promise to contribute to the control of cancer.

Evaluation of the antitumoral potential of different nitric oxide-donating non-steroidal anti-inflammatory drugs (NO-NSAIDs) on human urological tumor cell lines

Our work aimed at identifying the antitumoral potential of new nitric oxide (NO)-releasing non-steroidal anti-inflammatory drug (NSAID) derivatives on human prostate and bladder carcinoma cell lines. Among all molecules tested, two sulindac derivatives, NCX 1102 ((Z)-5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl] methylene]-1H-indene-3-acetic acid 4-(nitrooxy)butyl ester) and NCX 1105 ((Z)-5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl] methylene]-1H-indene-3-acetic acid 6-(nitrooxymethyl)-2-methylpyrydyl ester hydrochloride), were the most cytotoxic compounds. In contrast to its parent molecule sulindac, cell cycle analysis showed that NCX 1102 led to cell accumulation in the G2-M transition stage in all cell lines, and induced apoptosis in five out of the six cell lines. Thus, NO-NSAIDs may be useful for the elaboration of new therapeutic strategies in the management of bladder and prostate cancer.

NO-donating nonsteroidal antiinflammatory drugs (NSAIDs) inhibit colon cancer cell growth more potently than traditional NSAIDs: a general pharmacological property?

The novel nitric oxide-donating nonsteroidal antiinflammatory drugs (NO-NSAIDs), consisting of a traditional NSAID to which a NO releasing moiety is covalently attached, may have an important role in colon cancer prevention and/or treatment. Preclinical studies have shown that NO-aspirin (NO-ASA) is more potent than traditional ASA in preventing colon cancer. Preclinical and clinical studies have also documented its superior safety, compared to traditional ASA. To evaluate the role of this structural modification on the cancer cell growth inhibitory effect of NSAIDs, we studied seven pairs of traditional NSAIDs (ASA, salicylic acid, indomethacin, sulindac, ibuprofen, flurbiprofen, piroxicam) and their corresponding NO-NSAIDs. All NO-NSAIDs (except NO-piroxicam which is a salt and not a true NO-NSAID) have greater potency in inhibiting HT-29 and HCT-15 colon cancer cell growth compared to their NSAID counterparts: the IC 50s of the NO-NSAIDs were enhanced between 7- and 689-fold in HT-29 cells and 1.7- to 1083-fold in HCT-15 cells over those of the corresponding NSAIDs. Their growth inhibitory effect is due to a profound cell kinetic effect consisting of reduced cell proliferation and enhanced cell death. Since HT-29 cells express cyclooxygenases but HCT-15 do not, this effect appears independent of cyclooxygenase in the colon cancer cells. Thus the structural modification of these traditional NSAIDs leading to NO-NSAIDs enhances their potency in inhibiting colon cancer cell growth. Our findings suggest that the enhanced potency imparted on NSAIDs by this structural modification represents a pharmacological property that may be a general one for this class of compounds.

Nitrosulindac (NCX 1102): a new nitric oxide-donating non-steroidal anti-inflammatory drug (NO-NSAID), inhibits proliferation and induces apoptosis in human prostatic epithelial cell lines.

The aim of our study was to explore the anti-tumoral potential of the Nitric Oxide-Donating Non-Steroidal Anti-Inflammatory Drugs (NO-NSAID) NCX1102 (nitrosulindac), on three human prostatic epithelial cell lines at varying degree of transformation (PNT1A, LNCaP, and PC3). Cytotoxicity, anti-proliferative effects, cell-cycle alterations, morphological changes, and apoptosis were investigated after treatment with nitrosulindac in comparison to the native molecule sulindac. Involvement of the polyamine pathway in the action of nitrosulindac was also examined. Nitrosulindac but not sulindac exerted a cytotoxic effect on all cell lines and an anti-proliferative effect on LNCaP and PC3 cells only. Nitrosulindac differentially altered the cell cycle, induced mitotic arrest and displayed a pro-apoptotic activity in all cell lines. Finally, the polyamine pathway does not seem to be involved in the mechanism of nitrosulindac action. Our results demonstrate the anti-proliferative and proapoptotic activity of nitrosulindac on prostate cancer cell lines and suggest its potential interest for new strategies in the management of prostate cancer.

Nitric oxide-donating non-steroidal anti-inflammatory drugs: the case of nitroderivatives of aspirin

Nitric oxide (NO) acts as a key signalling mechanism in a number of cells and tissues in the mammalian organism. Modulation of the biosynthesis of NO has emerged to be relevant to the treatment of a variety of human diseases. In the attempt to reduce the serious side effects of non-steroidal anti-inflammatory drugs (NSAIDs), especially in the gastrointestinal tract, a NO-releasing moiety has been linked to conventional NSAIDs. A prototypical example is that of NO-releasing derivatives of aspirin. Thanks to the cytoprotective action of NO such compounds do not produce gastric damage and are emerging as an interesting novel group of drugs for their unique pharmacological properties.