The action of chelating agents in the removal of copper from ceruloplasmin An in vitro study

Jackson, Graham E.

doi:10.1016/0014-5793(78)80323-8

Cited by 32 publications

(6 citation statements)

References 17 publications

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“…It should be noted that almost all copper in vivo is bound to the copper carrying protein ceruloplasmin and/or albumin and that the concentration of free copper is very low. Each ceruloplasmin binds about six to seven copper atoms although it has been suggested that at least one of the copper atoms is loosely bound and therefore could be available for catalyzing D-pen oxidation [36,37]. The binding of albumin to copper is much weaker compared to ceruloplasmin; thus, the ability of D-pen to remove excess copper in Wilson's disease could be due to its ability to interact with albumin and remove albumin bound copper [37][38][39].…”

Section: Effect Of Time Of Incubation and Concentration Of Cupric Sulmentioning

confidence: 99%

An investigation into copper catalyzed D-penicillamine oxidation and subsequent hydrogen peroxide generation

Gupte

Mumper

2007

Journal of Inorganic Biochemistry

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Section: Effect Of Time Of Incubation and Concentration Of Cupric Sulmentioning

confidence: 99%

An investigation into copper catalyzed D-penicillamine oxidation and subsequent hydrogen peroxide generation

Gupte

Mumper

2007

Journal of Inorganic Biochemistry

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“…The effective combination of two ligands to enhance chelation rates (MLT) has been demonstrated for a range of metals 14. Typical examples are nitrilotriacetate (NTA) iron shuttling from transferrin to DFO 15, penicillamine/diethylene triamine pentaacetic acid for copper removal 16 and salicylic acid/EDTA for plutonium removal 17.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms for the shuttling of plasma non-transferrin-bound iron (NTBI) onto deferoxamine by deferiprone

Evans

Kayyali

Hider

et al. 2010

Translational Research

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In iron overload conditions, plasma contains non-transferrin bound iron species, collectively referred to as plasma NTBI. These include iron-citrate species, some of which are protein bound. Because NTBI is taken into tissues susceptible to iron loading, its removal by chelation is desirable but only partial using standard deferoxamine (DFO) therapy. Speciation plots suggest that, at clinically achievable concentrations, deferiprone (DFP) will shuttle iron onto DFO to form feroxamine (FO), but whether NTBI chelation is enhanced to therapeutically relevant rates is unknown. As FO is highly stable, kinetic measurements of FO formation by HPLC or by stoppedflow spectrometry is achievable. In serum from thalassemia major patients, supplemented with 10µM DFO, FO formation paralleled NTBI removal but never exceeded 50% of potentially available NTBI: approximately one third of NTBI was chelated rapidly but only 15% of the remainder at 20h. Addition of DFP increased the magnitude of the slower component, with increments in FO formation equivalent to complete NTBI removal by 8h. This shuttling effect was absent in serum from healthy control subjects, indicating no transferrin iron removal. Studies with iron-citrate solutions also showed biphasic chelation by DFO, the slow component being accelerated by the addition of DFP, with optimal enhancement at 30µM. Physiological concentrations of albumin also enhanced DFO chelation from iron citrate, and co-addition of DFP further accelerated this effect. We conclude that at clinically relevant concentrations, DFP enhances plasma NTBI chelation with DFO by rapidly accessing and shuttling NTBI fractions that are otherwise only slowly available to DFO.

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“…The majority of in vivo copper is bound to either ceruloplasmin or albumin with a much smaller fraction being labile copper. Each ceruloplasmin protein has the ability to bind 8 copper atoms, however it is known that only 6 are tightly bound at physiologic conditions and at least one is exchangeable and available for chemical reaction [40]. Previous studies have shown the generation of H 2 O 2 by DPEN in the presence of physiologically relevant concentrations of ceruloplasmin [15].…”

Section: Discussionmentioning

confidence: 99%

D-penicillamine combined with inhibitors of hydroperoxide metabolism enhances lung and breast cancer cell responses to radiation and carboplatin via H 2 O 2 -mediated oxidative stress

Sciegienka

Solst

Falls

et al. 2017

Free Radical Biology and Medicine

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D-penicillamine (DPEN), a copper chelator, has been used in the treatment of Wilson's disease, cystinuria, and rheumatoid arthritis. Recent evidence suggests that DPEN in combination with biologically relevant copper (Cu) concentrations generates H2O2 in cancer cell cultures, but the effects of this on cancer cell responses to ionizing radiation and chemotherapy are unknown. Increased steady-state levels of H2O2 were detected in MB231 breast and H1299 lung cancer cells following treatment with DPEN (100 μM) and copper sulfate (15 μM). Clonogenic survival demonstrated that DPEN-induced cancer cell toxicity was dependent on Cu and was significantly enhanced by depletion of glutathione [using buthionine sulfoximine (BSO)] as well as inhibition of thioredoxin reductase [using Auranofin (Au)] prior to exposure. Treatment with catalase inhibited DPEN toxicity confirming H2O2 as the toxic species. Furthermore, pretreating cancer cells with iron sucrose enhanced DPEN toxicity while treating with deferoxamine, an Fe chelator that inhibits redox cycling, inhibited DPEN toxicity. Importantly, DPEN also demonstrated selective toxicity in human breast and lung cancer cells, relative to normal untransformed human lung or mammary epithelial cells and enhanced cancer cell killing when combined with ionizing radiation or carboplatin. Consistent with the selective cancer cell toxicity, normal untransformed human lung epithelial cells had significantly lower labile iron pools than lung cancer cells. These results support the hypothesis that DPEN mediates selective cancer cell killing as well as radio-chemo-sensitization by a mechanism involving metal ion catalyzed H2O2-mediated oxidative stress and suggest that DPEN could be repurposed as an adjuvant in conventional cancer therapy.

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The action of chelating agents in the removal of copper from ceruloplasmin An in vitro study

Cited by 32 publications

References 17 publications

An investigation into copper catalyzed D-penicillamine oxidation and subsequent hydrogen peroxide generation

An investigation into copper catalyzed D-penicillamine oxidation and subsequent hydrogen peroxide generation

Mechanisms for the shuttling of plasma non-transferrin-bound iron (NTBI) onto deferoxamine by deferiprone

D-penicillamine combined with inhibitors of hydroperoxide metabolism enhances lung and breast cancer cell responses to radiation and carboplatin via H 2 O 2 -mediated oxidative stress

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