Cellular association, intracellular distribution, and efflux of auranofin via sequential ligand exchange reactions

Snyder, Rosanne M.; Mirabelli, Christopher K.; Crooke, Stanley T.

doi:10.1016/0006-2952(86)90078-x

Cited by 96 publications

(64 citation statements)

References 14 publications

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“…This discrepancy is likely to have been caused by the presence of 5% FCS in the medium that we used to add auranofin to the cells, while serumfree medium was used in the previous study. Sulfhydryl group of albumin in FCS was shown to significantly interfere with cellular association of auranofin gold, and only a fraction of the auranofin gold is taken up by the cells in the presence of FCS (42). Considering that whole blood levels of gold in RA patients treated with auranofin are 0.5-7.5 M (43), the concentrations of auranofin used in this study should be in the range that is relevant to its in vivo effect.…”

Section: Discussionmentioning

confidence: 99%

Thiol-Reactive Metal Compounds Inhibit NF-κB Activation by Blocking IκB Kinase

Jeon

Jeong

Jue

2000

The Journal of Immunology

214

174

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Gold compounds are used in the treatment of rheumatoid arthritis. NF-κB is a transcription factor implicated in the expression of many inflammatory genes. NF-κB is activated by signal-induced phosphorylation and subsequent degradation of inhibitory IκB (inhibitory protein that dissociates from NF-κB) proteins, and a multisubunit IκB kinase (IKK) has been identified previously. We tested the effect of various gold compounds on the activation of NF-κB and IKK in LPS-stimulated RAW 264.7 mouse macrophages. A lipophilic gold compound, auranofin, suppressed the LPS-induced increase of nuclear κB-binding activity, degradation of IκB proteins, and IKK activation. Auranofin also blocked IKK activation induced by TNF and PMA/ionomycin, suggesting that the target of auranofin action is common among these diverse signal pathways. In vitro IKK activity was suppressed by addition of hydrophilic gold compounds, such as aurothiomalate, aurothioglucose, and AuCl3. Other thiol-reactive metal ions such as zinc and copper also inhibited IKK activity in vitro, and induction of IKK in LPS-stimulated macrophages. In vitro IKK activity required the presence of reducing agent and was blocked by addition of thiol group-reactive agents. Two catalytic subunits of IKK complex, IKKα and IKKβ, were both inhibited by these thiol-modifying agents, suggesting the presence of a cysteine sulfhydryl group in these subunits, which is critical for enzyme activity. The antiinflammatory activity of gold compounds in the treatment of rheumatoid arthritis may depend on modification of this thiol group by gold.

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Section: Discussionmentioning

confidence: 99%

Thiol-Reactive Metal Compounds Inhibit NF-κB Activation by Blocking IκB Kinase

Jeon

Jeong

Jue

2000

The Journal of Immunology

214

174

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“…Furthermore the uptake half-life varies with size, with smaller nanoparticles taken up the fastest (t ½ = 1.9-2.2 h) [49]. By comparison, it has been reported that auranofin enters cells by the sulfhydryl shuttle model, where the Au(PEt) 3 + fragment binds to a membrane transport protein through a thiol group and is subsequently transported through the membrane [50]. It is possible that the other gold(I) drugs follow a similar mechanism, and thus may partially explain why Au NPs are taken up in more significant quantities.…”

Section: Cellular Gold Uptakementioning

confidence: 99%

An investigation into the interactions of gold nanoparticles and anti-arthritic drugs with macrophages, and their reactivity towards thioredoxin reductase

James

Sluyter

et al. 2015

Journal of Inorganic Biochemistry

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“…Snyder et al (1986) proposed a novel transport mechanism-the "sulfhydryl shuttle"-for the membrane transport of Auranofin 9, an antiarthritic agent, into macrophage cells. They suggest that the compound shuttles from albumin or cysteine to membrane -SH groups, and thence is internalized.…”

Section: New Considerations Regarding Mn Transportmentioning

confidence: 99%

“…Interestingly, Haest et al (1977) found that approximately 80% of -SH groups in the erythrocyte membrane are close enough to each other to allow chemical interactions. Snyder et al (1986) used mainly indirect evidence to support this model. The key data was the observation that Nethylmaleimide (NEM) blocked uptake of Auranofin 9, whereas metabolic inhibitors, such as 2,4-dinitrophenol (DNP) and sodium fluoride (NaF), did not exert an inhibitory effect.…”

Section: New Considerations Regarding Mn Transportmentioning

confidence: 99%

“…These results suggest that binding of membrane -SH by NEM blocked the "sulfhydryl shuttle", and that active transport processes of phagocytosis or endocytosis were not a part of the process. This feature led Snyder et al (1986) to suggest that a "sulfhydryl shuttle" may comprise a generic phenomenon for transport, whereby, closely apposed fixed membrane -SH groups are "shuttling" solutes across the BBB. Gerson and Shaikh (1984) have published evidence in support of Cd2+ entry into hepatocytes by an -SH carrier.…”

Section: New Considerations Regarding Mn Transportmentioning

confidence: 99%

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Manganese and its Role in Parkinson’s Disease: From Transport to Neuropathology

et al. 2009

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Abstract:The purpose of this review is to highlight recent advances in the neuropathology associated with Mn exposures. We commence with a discussion on occupational manganism and clinical aspects of the disorder. This is followed by novel considerations on Mn transport (see also chapter by Yokel, this volume), advancing new hypotheses on the involvement of several transporters in Mn entry into the brain. This is followed by a brief description of the effects of Mn on neurotransmitter systems that are putative modulators of dopamine (DA) biology (the primary target of Mn neurotoxicity), as well as its effects on mitochondrial dysfunction and disruption of cellular energy metabolism. Next, we discuss inflammatory activation of glia in neuronal injury and how disruption of synaptic transmission and glial-neuronal communication may serve as underlying mechanisms of Mn-induced neurodegeneration commensurate with the cross-talk between glia and neurons. We conclude with a discussion on therapeutic aspects of Mn exposure. Emphasis is directed at treatment modalities and the utility of chelators in attenuating the neurodegenerative sequelae of exposure to Mn. For additional reading on several topics inherent to this review as well as others, the reader may wish to consult Aschner and Dorman (Toxicological Review 25:147-154, 2007) and Bowman et al. (Metals and neurodegeneration, 2009).

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Cellular association, intracellular distribution, and efflux of auranofin via sequential ligand exchange reactions

Cited by 96 publications

References 14 publications

Thiol-Reactive Metal Compounds Inhibit NF-κB Activation by Blocking IκB Kinase

Thiol-Reactive Metal Compounds Inhibit NF-κB Activation by Blocking IκB Kinase

An investigation into the interactions of gold nanoparticles and anti-arthritic drugs with macrophages, and their reactivity towards thioredoxin reductase

Manganese and its Role in Parkinson’s Disease: From Transport to Neuropathology

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