Co-Administration of Nitric Oxide-Aspirin (NCX-4016) and Aspirin Prevents Platelet and Monocyte Activation and Protects Against Gastric Damage Induced by Aspirin in Humans

Fiorucci, Stefano; Mencarelli, Andrea; Meneguzzi, Alessandra; Lechi, Alessandro; Renga, Barbara; Soldato, Piero Del; Morelli, Antonio; Minuz, Pietro

doi:10.1016/j.jacc.2004.03.079

Cited by 37 publications

(31 citation statements)

References 35 publications

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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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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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“…The adjunct of a NO-moiety to NSAIDs has been recently proposed and showed to enhance anti-inflammatory, antithrombotic, and analgesic effects of the parent drugs [12,13] without gastrolesivity [10]. NORA has been shown to elicit significant vascular (arterial) relaxing response, to protect endothelial cells against apoptosis and to reduce oxidative stress in experimental studies [7,8,16,17].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a new family of nitric oxide-donating non-steroid anti-inflammatory drugs has been described. These compounds showed to enhance antiinflammatory, antithrombotic, and analgesic effects of the parent drugs [7][8][9][10][11][12][13]. Therefore, we sought to elucidate the effects of NO-releasing aspirin (NORA) in terms of evoked functional response of venous segments harvested in DM or control patients undergoing CABG.…”

Section: Introductionmentioning

confidence: 99%

Functional effects of nitric oxide-releasing aspirin on vein conduits of diabetic patients undergoing CABG

Lorusso¹,

Cicco²,

Beghi³

et al. 2007

International Journal of Cardiology

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“…In this regard, in the last decade two major strategies have emerged as stateof-the-art concepts: (1) the development of selective inhibitors of COX-2, the coxibs (for a review, see [24]); (2) the development of novel chemical entities obtained by the coupling of an NSAIDs to a ''donor molecule'' that will release NO and H 2 S in biological fluids [28,[30][31][32][33][34][35]. The first members in this class of novel NSAIDs are the socalled NO-NSAIDs, or COX-inhibiting NO donors [28].…”

Section: Gastrointestinal Injury Induced By Acetylsalicylic Acid Nonsmentioning

confidence: 99%

Bile acid activated receptors are targets for regulation of integrity of gastrointestinal mucosa

et al. 2015

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Bile acids are the end product of cholesterol metabolism. Synthesized in the liver, primary bile acids are secreted by hepatocytes and are transformed by intestinal microbiota into secondary bile acids. In addition to their role in cholesterol and lipid absorption, bile acids act as signaling molecules activating a family of nuclear and G-protein-coupled receptors collectively known as bile acid activated receptors (BARs). These receptors are expressed at high density in enterohepatic tissues, but their expression occurs throughout the body and their activation mediates regulatory functions of bile acids on lipids and glucose metabolism and immunity. In the gastrointestinal tract, BARs maintain intestinal integrity, and their deletion makes the intestine more susceptible to the damage caused by acetylsalicylic acid and nonsteroidal anti-inflammatory drugs (NSAIDs). Deficiency in farnesoid X receptor and G-protein-coupled bile acid receptor 1 genes alters the expression/activity of cystathione c-lyase and endothelial nitric oxide synthase, two genes involved in the synthesis of hydrogen sulfide and nitric oxide, i.e., two gaseous mediators that have been shown to be essential in maintaining the intestinal homeostasis. In addition, farnesoid X receptor regulates the expression of transporters required for secretion of phospholipid by hepatocytes. Because phospholids attenuate intestinal injury caused by acetylsalicylic acid and NSAIDs, BAR agonism could be exploited to protect the intestinal mucosa against injury caused by anti-inflammatory medications. This approach might be useful in the prevention of so-called NSAID enteropathy, a common clinical condition occurring in long-term users of NSAIDs, which is not effectively prevented either by cotreatment with proton pump inhibitors or by the use of coxibs.

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Co-Administration of Nitric Oxide-Aspirin (NCX-4016) and Aspirin Prevents Platelet and Monocyte Activation and Protects Against Gastric Damage Induced by Aspirin in Humans

Abstract: NCX-4016 is equally effective as aspirin in inhibiting cyclooxygenase activity. However, NCX-4016 causes less gastric damage and prevents monocyte activation. Larger multicenter trials are warranted to establish clinical efficacy and safety of NCX-4016.

Cited by 37 publications

References 35 publications

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

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

Functional effects of nitric oxide-releasing aspirin on vein conduits of diabetic patients undergoing CABG

Bile acid activated receptors are targets for regulation of integrity of gastrointestinal mucosa

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