Biochemistry of Nitric Oxide and Its Redox-Activated Forms

Stamler, Jonathan S.; Singel, David J.; Loscalzo, Joseph

doi:10.1126/science.1281928

Cited by 2,593 publications

(1,535 citation statements)

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“…This increased pool of extracellular NO was contradictory to the lower radiosensitising activity, which again confirms the lack of correlation between NO production and radiosensitising activity for bioreductive NO donors. Endogenously formed GSNO is conceivably the major adduct of natural thiols, with nitrosonium cation accumulated in cells after exposure to NO (Ignarro et al, 1981;Stamler et al, 1992;Clancy et al, 1994). As such, it may also be involved in the trapping and storing of SNP-derived NO adducts in hypoxic cells, thereby supporting delayed radiosensitisation.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic radiosensitivity of human pancreatic tumour cells and the radiosensitising potency of the nitric oxide donor sodium nitroprusside

Verovski¹,

Berge²,

Soete³

et al. 1996

Br J Cancer

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Summary A panel of eight human pancreatic tumour cell lines displayed high intrinsic radioresistance, with mean inactivation doses between 2.4 and 6.5 Gy, similar to those reported for melanoma and glioblastoma. The radiosensitising potency of sodium nitroprusside, a bioreductive nitric oxide donor, was assessed in a model of metabolism-induced hypoxia in a cell micropellet. Sodium nitroprusside at 0.1 mm revealed a radiosensitising effect with an overall enhancement ratio of 1.9 compared with 2.5 for oxygen. Radiosensitising activity correlated with the enhancement of single-strand DNA breakage caused by radiation. In suspensions with cell densities of between 3% and 30% (v/v), the half-life of sodium nitroprusside decreased from 31 to 3.2 min, suggesting a value of around min for micropellets. Despite this variation, the radiosensitising activity was similar in micropellets and in diluted cell suspensions. S-nitroso-L-glutathione was found to possess radiosensitising activity, consistent with a possible role of natural thiols in the storing of radiobiologically active nitric oxide adducts derived from sodium nitroprusside. As measured by a nitric oxide-specific microsensor, activation of sodium nitroprusside occurred by bioreduction, whereas S-nitroso-L-glutathione showed substantial spontaneous decomposition. Both agents appear to exert radiosensitising action through nitric oxide as its scavenging by carboxy phenyltetramethylimidazolineoxyl N-oxide (carboxy-PTIO) and oxyhaemoglobin resulted in attenuated radiosensitisation. Sodium nitroprusside was at least 10-fold more potent than etanidazole, a 2-nitroimidazole used as a reference. Our data suggest that sodium nitroprusside, a drug currently used for the treatment of hypertension, is a potential tumour radioresponse modifier.Keywords: human pancreatic tumour; hypoxic cell radiosensitisation; sodium nitroprusside; S-nitroso-Lglutathione; nitric oxide Adenocarcinoma of the pancreas is the fourth leading cause of cancer-related deaths and represents a type of tumour refractory to radiotherapy (Brennan et al., 1993). The poor response rates to external beam radiotherapy may be explained by the proximity of many dose-limiting organs and possibly by intrinsic and hypoxia-induced radioresistance as well. The latter factor is of considerable interest, because hypoxic cells can be specifically targeted by electron-affinic compounds such as nitroimidazoles and bioreductive cytotoxins (Adams, 1992).Nitric oxide (NO) is a relatively long-life radical generated endogenously by nitric oxide synthases, and has been implicated in signal transduction in the nervous and vascular system and as a cytotoxin in pathophysiological processes related to cellular immunity and hypoxia -reoxygenation injury (Knowles and Moncada, 1994). NO, in gaseous form or released chemically from the NONOate complex DEA/ NO, has also been shown to radiosensitise hypoxic cells. The mechanism of NO-mediated radiosensitisation has been postulated to be the fixation of radiation-induced DNA damage, th...

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Section: Discussionmentioning

confidence: 99%

Intrinsic radiosensitivity of human pancreatic tumour cells and the radiosensitising potency of the nitric oxide donor sodium nitroprusside

Verovski¹,

Berge²,

Soete³

et al. 1996

Br J Cancer

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“…6,8,9,12,14,16,17,[19][20][21][22]48 Over the past decade, accumulating evidence has suggested that S-nitrosylation can regulate the biological activity of a great variety of proteins, in some ways akin to phosphorylation. 10,[49][50][51][52][53][54] Chemically, NO is often a good 'leaving group,' facilitating further oxidation of critical thiol to disulfide bonds among neighboring (vicinal) cysteine residues or, via reaction with ROS, to sulfenic (ÀSOH), sulfinic (ÀSO 2 H), or sulfonic (ÀSO 3 H) acid derivatization of the protein. 19,20,22,55 Alternatively, S-nitrosylation may possibly produce a nitroxyl disulfide, in which the NO group is shared by close cysteine thiols.…”

Section: Protein S-nitrosylation Affects Neuronal Survivalmentioning

confidence: 99%

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

Nakamura

Lipton

2007

Cell Death Differ

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Although activation of glutamate receptors is essential for normal brain function, excessive activity leads to a form of neurotoxicity known as excitotoxicity. Key mediators of excitotoxic damage include overactivation of N-methyl-D-aspartate (NMDA) receptors, resulting in excessive Ca 2 þ influx with production of free radicals and other injurious pathways. Overproduction of free radical nitric oxide (NO) contributes to acute and chronic neurodegenerative disorders. NO can react with cysteine thiol groups to form S-nitrosothiols and thus change protein function. S-nitrosylation can result in neuroprotective or neurodestructive consequences depending on the protein involved. Many neurodegenerative diseases manifest conformational changes in proteins that result in misfolding and aggregation. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. Molecular chaperones -such as protein-disulfide isomerase, glucose-regulated protein 78, and heat-shock proteins -can provide neuroprotection by facilitating proper protein folding. Here, we review the effect of S-nitrosylation on protein function under excitotoxic conditions, and present evidence that NO contributes to degenerative conditions by S-nitrosylating-specific chaperones that would otherwise prevent accumulation of misfolded proteins and neuronal cell death. In contrast, we also review therapeutics that can abrogate excitotoxic damage by preventing excessive NMDA receptor activity, in part via S-nitrosylation of this receptor to curtail excessive activity.

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“…Given the rich chemistry (for review, see ref. 60) and biochemistry of NO, and the variety of cell types that produce this radical, it is not surprising that NO influences a wide range of physiologic processes. These are listed in Table 2.…”

Section: Biochemical Properties Of Nitric Oxidementioning

confidence: 99%