Nitroxyl inhibits breast tumor growth and angiogenesis

Norris, Andrew J.; Sartippour, Maryam R.; Lu, Ming; Park, Taylor; Rao, Jian Yu; Jackson, Matthew I.; Fukuto, Jon M.; Brooks, Mai N.

doi:10.1002/ijc.23305

Cited by 86 publications

(91 citation statements)

References 32 publications

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“…Inhibition of enzymes containing critical thiols by HNO can affect alcohol metabolism (30, 118) as well as DNA repair, apoptosis, and glycolysis (95,120,153,155), which affect tumor progression. The cardiovascular effects of HNO donors are driven by thiolmodifications, particularly of calcium channels such as the ryanodine receptor and SERCA2a calcium pump (20, 160).…”

Section: Resultsmentioning

confidence: 99%

“…Consistent with this idea, HNO has been shown to inhibit breast (120) and neuroblastoma (155) cancer proliferation in mouse xenografts as well as in culture. Reduced blood vessel density with the tumors was accompanied by reduced levels of circulating vascular endothelial growth factor and in total hypoxia-inducible factor 1a protein (120). As a result, an increase in apoptosis and the apoptotic factor caspase-9 were observed.…”

Section: Cancer Therapymentioning

confidence: 93%

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The Specificity of Nitroxyl Chemistry Is Unique Among Nitrogen Oxides in Biological Systems

Flores-Santana

Salmon

Donzelli

et al. 2011

Antioxidants & Redox Signaling

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The importance of nitric oxide in mammalian physiology has been known for nearly 30 years. Similar attention for other nitrogen oxides such as nitroxyl (HNO) has been more recent. While there has been speculation as to the biosynthesis of HNO, its pharmacological benefits have been demonstrated in several pathophysiological settings such as cardiovascular disorders, cancer, and alcoholism. The chemical biology of HNO has been identified as related to, but unique from, that of its redox congener nitric oxide. A summary of these findings as well as a discussion of possible endogenous sources of HNO is presented in this review.

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Section: Resultsmentioning

confidence: 99%

Section: Cancer Therapymentioning

confidence: 93%

The Specificity of Nitroxyl Chemistry Is Unique Among Nitrogen Oxides in Biological Systems

Flores-Santana

Salmon

Donzelli

et al. 2011

Antioxidants & Redox Signaling

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“…Given the current excitement regarding the potential of HNO as a therapeutic agent, for example for the treatment of heart failure (10,11,16), and its recent success in inhibiting angiogenesis and breast cancer growth in vitro (15), the approach outlined in this study should be of use to researchers in the biomedical community interested in further elucidating the targets and mechanism of action of nitroxylation. This mass spectrometry-based approach, applicable to a single protein or at a proteome-wide level, has for the first time allowed the identification of HNO-induced modifications on proteins in a biologically relevant setting.…”

Section: Global Proteome Analysis For Discovery Of Hno-induced Modifimentioning

confidence: 99%

Identification of Nitroxyl-induced Modifications in Human Platelet Proteins Using a Novel Mass Spectrometric Detection Method

Hoffman

Walsh

Rogalski

et al. 2009

Molecular & Cellular Proteomics

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Nitroxyl (HNO) exhibits many important pharmacological effects, including inhibition of platelet aggregation, and the HNO donor Angeli's salt has been proposed as a potential therapeutic agent in the treatment of many diseases including heart failure and alcoholism. Despite this, little is known about the mechanism of action of HNO, and its effects are rarely linked to specific protein targets of HNO or to the actual chemical changes that proteins undergo when in contact with HNO. Here we study the presumed major molecular target of HNO within the body: protein thiols. Cysteine-containing tryptic peptides were reacted with HNO, generating the sulfinamide modification and, to a lesser extent, disulfide linkages with no other long lived intermediates or side products. The sulfinamide modification was subjected to a comprehensive tandem mass spectrometric analysis including MS/MS by CID and electron capture dissociation as well as an MS 3 analysis. These studies revealed a characteristic neutral loss of HS(O)NH 2 (65 Da) that is liberated from the modified cysteine upon CID and can be monitored by mass spectrometry. Upon storage, partial conversion of the sulfinamide to sulfinic acid was observed, leading to coinciding neutral losses of 65 and 66 Da (HS(O)OH). Validation of the method was conducted using a targeted study of nitroxylated glyceraldehyde-3-phosphate dehydrogenase extracted from Angeli's salt-treated human platelets. In these ex vivo experiments, the sample preparation process resulted in complete conversion of sulfinamide to sulfinic acid, making this the sole subject of further ex vivo studies. A global proteomics analysis to discover platelet proteins that carry nitroxyl-induced modifications and a mass spectrometric HNO dose-response analysis of the modified proteins were conducted to gain insight into the specificity and selectivity of this modification. These methods identified 10 proteins that are modified dose dependently in response to HNO, whose functions range from metabolism and cytoskeletal rearrangement to signal transduction, providing for Nitric oxide (NO)1 has emerged as an important physiological signaling molecule, particularly in the vascular, neuronal, and immune systems. NO regulates many processes including platelet function, vascular tone, and leukocyte recruitment mainly through the cGMP second messenger system (1). More recent studies have shown that nitric oxide can react directly with a number of different biological species including metal centers of proteins, nucleophilic amino acid residues (nitrosation/S-nitrosylation), and aromatic amino acid residues (nitration) (2, 3), and the products of these reactions have been analyzed by mass spectrometry (4 -8). The biological relevance of these reactions is slowly coming to light, and NO-mediated S-nitrosylation has now been linked to a number of diseases including diabetes, multiple sclerosis, cystic fibrosis, and asthma (9).Nitroxyl (HNO/NO Ϫ ), an alternative redox form of NO, has only recently begun to draw attention in th...

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“…Much recent interest in HNO-releasing compounds results from their potential pharmacological use for cardiovascular disorders (16)(17)(18), cancer (19), and alcoholism (20,21). But the significance of "free" HNO in nature is as yet uncertain (22).…”

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confidence: 99%

Nitrosyl hydride (HNO) replaces dioxygen in nitroxygenase activity of manganese quercetin dioxygenase

Kumar

Zapata

Ramirez

et al. 2011

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

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Quercetin dioxygenase (QDO) catalyzes the oxidation of the flavonol quercetin with dioxygen, cleaving the central heterocyclic ring and releasing CO. The QDO from Bacillus subtilis is unusual in that it has been shown to be active with several divalent metal cofactors such as Fe, Mn, and Co. Previous comparison of the catalytic activities suggest that Mn(II) is the preferred cofactor for this enzyme. We herein report the unprecedented substitution of nitrosyl hydride (HNO) for dioxygen in the activity of Mn-QDO, resulting in the incorporation of both N and O atoms into the product. Turnover is demonstrated by consumption of quercetin and other related substrates under anaerobic conditions in the presence of HNO-releasing compounds and the enzyme. As with dioxygenase activity, a nonenzymatic base-catalyzed reaction of quercetin with HNO is observed above pH 7, but no enhancement of this basal reactivity is found upon addition of divalent metal salts. Unique and regioselective N-containing products ( 14 N∕ 15 N) have been characterized by MS analysis for both the enzymatic and nonenzymatic reactions. Of the several metallo-QDO enzymes examined for nitroxygenase activity under anaerobic condition, only the Mn(II) is active; the Fe(II) and Co(II) substituted enzymes show little or no activity. This result represents an enzymatic catalysis which we denote nitroxygenase activity; the unique reactivity of the Mn-QDO suggests a metalmediated electron transfer mechanism rather than metal activation of the substrate's inherent base-catalyzed reactivity.nitroxyl | quercetinase D ioxygenases are enzymes that incorporate both atoms of dioxygen into a targeted substrate, e.g., the enzyme catechol 1,2-dioxygenase cleaves the C-C bond between catechol's two hydroxyl groups forming the dicarboxylate cis,cis-muconic acid (1). Although highly divergent, there are two broadly defined classes of nonheme dioxygenases: those that directly bind dioxygen at the metal center or those in which dioxygen binds to the substrate that has been activated by interaction with the metal center (2). Such questions also apply to quercetin dioxygenase (QDO), which catalyzes the oxidation of the flavonol quercetin (1) with dioxygen ( Fig. 1). During turnover, QDO cleaves the central heterocyclic ring of quercetin, releasing CO, and yielding the corresponding depside. The QDO from Bacillus subtilis is unusual in that it has been shown to be active with several divalent metal cofactors such as Cu, Fe, Mn, and Co. Comparison of the catalytic activities suggest that Mn(II) is the preferred cofactor for this enzyme (3).The simple molecule nitrosyl hydride (HNO) is the singly reduced and protonated form of nitric oxide, NO. HNO has garnered much interest because it demonstrates a physiological reactivity distinctly different from its congener nitric oxide (4, 5). In a series of papers, we have reported the preparation and characterization of the HNO adduct of myoglobin (HNO-Mb) by reduction of 7) and by trapping of free HNO by deoxymyoglobin (Mb-Fe II ) (8)...

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Nitroxyl inhibits breast tumor growth and angiogenesis

Cited by 86 publications

References 32 publications

The Specificity of Nitroxyl Chemistry Is Unique Among Nitrogen Oxides in Biological Systems

The Specificity of Nitroxyl Chemistry Is Unique Among Nitrogen Oxides in Biological Systems

Identification of Nitroxyl-induced Modifications in Human Platelet Proteins Using a Novel Mass Spectrometric Detection Method

Nitrosyl hydride (HNO) replaces dioxygen in nitroxygenase activity of manganese quercetin dioxygenase

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