IL-1β Converting Enzyme Is a Target for Nitric Oxide-Releasing Aspirin: New Insights in the Antiinflammatory Mechanism of Nitric Oxide-Releasing Nonsteroidal Antiinflammatory Drugs

Fiorucci, Stefano; Santucci, Luca; Cirino, Giuseppe; Mencarelli, Andrea; Familiari, L; Soldato, Piero Del; Morelli, Antonio

doi:10.4049/jimmunol.165.9.5245

Cited by 99 publications

(91 citation statements)

References 53 publications

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“…Additional evidence is given by the reduction in the antiaggregatory activity of NCX4106 in the presence of oxyhaemoglobin, a NO scavenger, or methylene blue (Lechi et al, 1996). Con®rming previous studies, we found that intracellular cyclic GMP is increased in adherent human monocytes up to 6 h after incubation with NCX4016 (Fiorucci et al, 2000b). The absence of any increase in this NO-induced intracellular signal may explain the reduction in NCX4016 activity after more prolonged incubation.…”

Section: Discussionsupporting

confidence: 84%

“…Moreover, NCX4017 which is similar to NCX4017 but is deprived of the NO-releasing moiety, dose-dependently decreases TXB 2 generation. It is worth noting that NCX4017 was shown to be cytotoxic in human monocytes after prolonged incubation, but this is not observed after a 6-h incubation period (Fiorucci et al, 2000b). In all the conditions where NO activity is prevented, NCX4016 proves less eective than ASA.…”

Section: Discussionmentioning

confidence: 92%

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NCX4016 (NO‐Aspirin) has multiple inhibitory effects in LPS‐stimulated human monocytes

Minuz

Degan

Gaino

et al. 2001

British J Pharmacology

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NCX4016 (2 acetoxy‐benzoate 2‐(2‐nitroxymethyl)‐phenyl ester, NicOx S.A., France) is an anti‐thrombotic agent, chemically related to acetylsalicylic acid (ASA) and able to release NO. We tested the effects of NCX4016 and ASA on the release of the thromboxane (TX) A2 metabolite TXB2, tumour necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), expression and activity of tissue factor (TF) in stimulated, adherent human monocytes. Both ASA and NCX4016 1 – 1000 μmol l−1 dose‐dependently reduced TXB2 concentration, measured by RIA in the supernatant of 10 μg ml−1 LPS‐stimulated cells. NCX4016 activity was comparable to that of equimolar ASA when incubation lasted 6 h (NCX4016 30 μmol l−1: −86.0±10.1%, NCX4016 300 μmol l−1: −92.2±9.0%, ASA 30 μmol l−1: −92.3±7.5%, ASA 300 μmol l−1: −97.3±1.0%, n=6, M±s.d.). Most of the activity of NCX4016 up to 100 μmol l−1 was prevented by 10 μmol l−1 ODQ, inhibitor of cyclic GMP. NCX4016 100 – 300 μmol l−1 reduced TNF‐α (NCX4016 300 μmol l−1=−77.2±19.9%, n=6) and IL‐6 (NCX4016 300 μmol l−1: −61.9±15.2%, n=6) in LPS stimulated monocytes while ASA had no significant effects. TF activity (NCX4016 300 μmol l−1: 53.7±39.9%, n=4) and immunoreactive TF (NCX4016 300 μmol l−1: −93.9±7.9%, n=7), measured in the supernatant of stimulated cells, were also dose‐dependently inhibited by NCX4016 but not by ASA. The present results indicate that NCX4016 inhibits TXA2 generation as well as cytokine release and TF in human monocytes partly via NO‐dependent mechanisms. NCX4016 may have a favourable profile of activities in the clinical setting of athero‐thrombosis. British Journal of Pharmacology (2001) 134, 905–911; doi:10.1038/sj.bjp.0704326

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 92%

NCX4016 (NO‐Aspirin) has multiple inhibitory effects in LPS‐stimulated human monocytes

Minuz

Degan

Gaino

et al. 2001

British J Pharmacology

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“…The drug has been shown to release sustained amounts of NO in vivo (14,15). Although the use of NSAIDs is limited by their gastrointestinal (GI) and renal toxicity, NOreleasing NSAIDs were shown to exert antiinflammatory and analgesic effects that were at least as potent as those of the parent drug, without causing GI tract toxicity (16)(17)(18)(19). The in vivo metabolism of these drugs has been established reasonably well in a rat model (14,20), except that the precise mechanism by which NO is released from the nitro moiety has yet to be understood.…”

Section: Effect Of Ncx-4016 On the Clonogenecity Of Hoccsmentioning

confidence: 99%

Reversal to cisplatin sensitivity in recurrent human ovarian cancer cells by NCX-4016, a nitro derivative of aspirin

Bratasz¹,

Weir

Parinandi

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Ovarian cancer is a gynecological malignancy that is commonly treated by cytoreductive surgery followed by cisplatin treatment. However, the cisplatin treatment, although successful initially, is not effective in the treatment of the recurrent disease that invariably surfaces within a few months of the initial treatment. The refractory behavior is attributed to the increased levels of cellular thiols apparently caused by the cisplatin treatment. This observation prompted us to choose a cytotoxic drug whose activity is potentiated by cellular thiols with enhanced specificity toward the thiol-rich cisplatin-resistant cells. We used NCX-4016 [2-(acetyloxy) benzoic acid 3-(nitrooxymethyl)phenyl ester], a derivative of aspirin containing a nitro group that releases nitric oxide in a sustained fashion for several hours in cells and in vivo, and we studied its cytotoxic efficacy against human ovarian cancer cells (HOCCs). Cisplatin-sensitive and cisplatin-resistant (CR) HOCCs were treated with 100 M NCX-4016 for 6 h, and͞or 0.5 g͞ml cisplatin for 1 h and assayed for clonogenecity. NCX-4016 significantly reduced the surviving fractions of cisplatin-sensitive (63 ؎ 6%) and CR (70 ؎ 10%) HOCCs. NCX-4016 also caused a 50% reduction in the levels of cellular glutathione in CR HOCCs. Treatment of cells with NCX-4016 followed by cisplatin showed a significantly greater extent of toxicity when compared with treatment of cells with NCX-4016 or cisplatin alone. In conclusion, this study showed that NCX-4016 is a potential inhibitor of the proliferation of CR HOCCs and thus might specifically kill cisplatin-refractory cancer cells in patients with recurrent ovarian cancer.cisplatin resistance ͉ glutathione ͉ nitric oxide ͉ cytotoxicity ͉ nonsteroidal antiinflammatory drug O varian cancer is the second most commonly diagnosed gynecological malignancy and the fourth leading cause of mortality among women in the United States (1). The high mortality rate is attributed to the lack of early diagnosis of the malignancy and difficulties associated with treatment. The standard treatment includes cytoreductive surgery followed by the administration of chemotherapeutic agents. Platinum-based compounds (e.g., cisplatin and carboplatin) in combination with taxanes (e.g., taxol or paclitaxel), anthracyclines (e.g., doxorubicin), or alkylating agents (e.g., melphalan) are administered to treat the advanced-stage disease (2). However, the overall clinical response with such treatments is only 40-60%. The primary factor that limits the success of chemotherapy in ovarian cancer is the acquired drug resistance in the tumor cell population. Administration of cisplatin results in the development of drug resistance in the cancer cells. Postulated mechanisms of drug resistance include decreased intracellular accumulation of the drug, increased levels of thiols, which inactivate the platinum compound, and the enhancement of DNA repair (3). Even a slight increase in the cisplatin resistance of the tumor may pose a clinically important problem requiring ...

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“…Coupling of a NO-releasing moiety to conventional nonsteroidal antiinflammatory drugs or other antiinflammatory drugs was attempted to reduce the gastrointestinal toxicity of these compounds (18). These new molecules have interesting properties, such as antioxidant activity, suppression of reactive oxygen species generation (19), inhibition of proinflammatory cytokine release by mononuclear cells (20), feedback inhibition of NOS2 catalytic activity (21), and suppression of cancer cell proliferation (22), all of which make them attractive and safe candidates for alleviating MSC-induced alterations of the immune system in tumor-bearing hosts. 13.…”

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confidence: 99%

Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination

Santo¹,

Serafini²,

Marigo³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

261

192

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Active suppression of tumor-specific T lymphocytes can limit the immune-mediated destruction of cancer cells. Of the various strategies used by tumors to counteract immune attacks, myeloid suppressors recruited by growing cancers are particularly efficient, often resulting in the induction of systemic T lymphocyte dysfunction. We have previously shown that the mechanism by which myeloid cells from tumor-bearing hosts block immune defense strategies involves two enzymes that metabolize L-arginine: arginase and nitric oxide (NO) synthase. NO-releasing aspirin is a classic aspirin molecule covalently linked to a NO donor group. NO aspirin does not possess direct antitumor activity. However, by interfering with the inhibitory enzymatic activities of myeloid cells, orally administered NO aspirin normalized the immune status of tumorbearing hosts, increased the number and function of tumorantigen-specific T lymphocytes, and enhanced the preventive and therapeutic effectiveness of the antitumor immunity elicited by cancer vaccination. Because cancer vaccines and NO aspirin are currently being investigated in independent phase I͞II clinical trials, these findings offer a rationale to combine these treatments in subjects with advanced neoplastic diseases.arginase ͉ immunosuppression ͉ myeloid cells ͉ nitric oxide ͉ immunotherapy I dentifying effective treatments for cancer is a clinical priority.Despite the plethora of evidence in preclinical models, the most advanced immunotherapy, either active or passive, has had limited success in human clinical trials (1). Basis for this conclusion appears to involve at least in part the progressive accumulation of myeloid cells, which exert a powerful inhibitory activity on antitumor lymphocytes as a function of tumor growth. In tumor-bearing hosts, for example, tumor progression is often associated with altered hematopoiesis, which leads to the accumulation of myeloid cells at the tumor site and in blood, secondary lymphoid organs, and bone marrow (2-4).Mouse myeloid cells express the CD11b and Gr-1 markers, have a mixed mature-immature myeloid phenotype, and are responsible for the induction of tumor-specific and nonspecific T cell dysfunctions, which are frequently observed not only in transplantable tumors but also in tumors spontaneously arising with transgenic expression of tissue-restricted oncogenes (2, 5). These cells have been termed myeloid suppressor cells (MSCs) and arise from bone marrow and other hematopoietic organs exposed to systemically released factors acting on myelomonocytic precursors (reviewed in refs. 2, 3, and 6). Moreover, MSCs are the final effectors of a circuit that negatively affects tumor immunity and that requires participation of natural killer T cells. Cytotoxic T lymphocyte (CTL)-mediated tumor immunosurveillance was recently shown to be down-regulated by TGF-␤ released by CD11b ϩ ͞Gr-1 ϩ cells, an event driven by cytokine IL-13 release from CD1d-restricted natural killer T cells (7). This circuit is activated very early in tumor progression and ...

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IL-1β Converting Enzyme Is a Target for Nitric Oxide-Releasing Aspirin: New Insights in the Antiinflammatory Mechanism of Nitric Oxide-Releasing Nonsteroidal Antiinflammatory Drugs

Cited by 99 publications

References 53 publications

NCX4016 (NO‐Aspirin) has multiple inhibitory effects in LPS‐stimulated human monocytes

NCX4016 (NO‐Aspirin) has multiple inhibitory effects in LPS‐stimulated human monocytes

Reversal to cisplatin sensitivity in recurrent human ovarian cancer cells by NCX-4016, a nitro derivative of aspirin

Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination

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