Bis-(diethyldithiocarbamato) copper complex: a new metabolite of disulfiram?

Johansson, Benny; Stankiewicz, Z.K.

doi:10.1016/0006-2952(85)90026-7

Cited by 42 publications

(17 citation statements)

References 13 publications

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“…The conversion of disulfiram into a copper complex in blood (which contains typically between 15 and 25 M copper) has been evaluated previously (36,54). Because the formation of a disulfiram-copper complex in vivo is likely (21,36,54), and since we found no significant activity toward M. tuberculosis in the absence of copper, the previously reported in vivo activity of disulfiram in macrophage and animal models is likely associated with its ability to form a copper complex. It is therefore intriguing to imagine that the various infection-associated copper reservoirs may activate/potentiate the antibacterial properties of disulfiram/DETC through formation of disulfiram-derived copper complexes.…”

Section: Discussionmentioning

confidence: 61%

See 1 more Smart Citation

Disulfiram and Copper Ions Kill Mycobacterium tuberculosis in a Synergistic Manner

Dalecki

Haeili

Shah

et al. 2015

Antimicrob Agents Chemother

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Section: Discussionmentioning

confidence: 61%

“…In contrast to many other dithiocarbamates and the prevailing opinion, disulfiram itself is a very poor metal chelator (36). The metal-complexing ability of disulfiram lies in the reduction of its disulfide bond, producing two molecules of diethyldithiocarbamate (DETC) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Disulfiram and Copper Ions Kill Mycobacterium tuberculosis in a Synergistic Manner

Dalecki

Haeili

Shah

et al. 2015

Antimicrob Agents Chemother

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“…The in vivo formation of the complex in patients taking disulfiram has also been observed. Low concentrations of the complex in the plasma obtained from patients treated with disulfiram may be due to the lipophilic character of the complex resulting in its distribution through the cell membrane or its decomposition into tissue [32]. Because Cu(EtDTC) 2 is a lipophilic and stable compound, it is the most absorbed form of disulfiram [33].…”

Section: Complex Formation In the Human Bodymentioning

confidence: 99%

Diethyldithiocarbamate complex with copper: the mechanism of action in cancer cells

Škrott

Cvek²

2012

MRMC

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The idea of "repurposing" of existing drugs provides an effective way to develop and identify new therapies. Disulfiram (Antabuse), a drug commonly used for the treatment of alcoholism, shows promising anticancer activity in both preclinical and clinical studies. In the human body, disulfiram is rapidly converted to its reduced metabolite, diethyldithiocarbamate. If copper ions are available, a bis(diethyldithiocarbamate)-copper(II) complex is formed. Disulfiram's selective anticancer activity is attributed to the copper(II) complex's ability to inhibit the cellular proteasome. It is assumed that the complex inhibits the proteasome by a mechanism that is distinct to the clinically used drug bortezomib, targeting the 19S rather than the 20S proteasome. This difference could be explained by inhibition of the JAMM domain of the POH1 subunit within the lid of the 19S proteasome.

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“…Kodama et al (20) and Munakata et al (21) demonstrated that the use of a combination of copper and disulfiram, a lipophilic chelator, improved copper deficiency in the brain of MD model mice (macular mice). Administered disulfiram is immediately converted into sodium diethyldithiocarbamate (DEDTC) by glutathione reductase, and the complex of copper and DEDTC can pass through the BBB (22)(23)(24). To advance these findings to clinical application, it is important to elucidate the time course of copper biodistribution with and without disulfiram.…”

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confidence: 99%

PET Imaging Analysis with ⁶⁴Cu in Disulfiram Treatment for Aberrant Copper Biodistribution in Menkes Disease Mouse Model

Nomura

Nozaki²,

Hamazaki

et al. 2014

J Nucl Med

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Menkes disease (MD), an X-linked recessive disorder of copper metabolism caused by mutations in the copper-transporting ATP7A gene, results in growth failure and severe neurodegeneration in early childhood. Subcutaneous copper-histidine injection is the standard treatment for MD, but it has limited clinical efficacy. Furthermore, long-term copper injection causes excess copper accumulation in the kidneys, resulting in renal dysfunction. To attempt to resolve this issue, we used PET imaging with 64 Cu to investigate the effects of disulfiram on copper biodistribution in living mice serving as an animal model for MD (MD model mice). Methods: Macular mice were used as MD model mice, and C3H/He mice were used as wild-type mice. Mice were pretreated with 2 types of chelators (disulfiram, a lipophilic chelator, and D-penicillamine, a hydrophilic chelator) 30 min before 64 CuCl 2 injection. After 64 CuCl 2 injection, emission scans covering the whole body were performed for 4 h. After the PET scans, the brain and kidneys were analyzed for radioactivity with γ counting and autoradiography. Results: After copper injection alone, marked accumulation of radioactivity ( 64 Cu) in the liver was demonstrated in wild-type mice, whereas in MD model mice, copper was preferentially accumulated in the kidneys (25.56 ± 3.01 percentage injected dose per gram [%ID/g]) and was detected to a lesser extent in the liver (13.83 ± 0.26 %ID/g) and brain (0.96 ± 0.08 %ID/g). Copper injection with disulfiram reduced excess copper accumulation in the kidneys (14.54 ± 2.68 %ID/g) and increased copper transport into the liver (29.42 ± 0.98 %ID/g) and brain (5.12 ± 0.95 %ID/g) of MD model mice. Copper injection with D-penicillamine enhanced urinary copper excretion and reduced copper accumulation in most organs in both mouse groups. Autoradiography demonstrated that disulfiram pretreatment induced copper transport into the brain parenchyma and reduced copper accumulation in the renal medulla. Conclusion: PET studies with 64 Cu revealed that disulfiram had significant effects on the copper biodistribution of MD. Disulfiram increased copper transport into the brain and reduced copper uptake in the kidneys of MD model mice. The application of 64 Cu PET for the treatment of MD and other copperrelated disorders may be useful in clinical settings.

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Bis-(diethyldithiocarbamato) copper complex: a new metabolite of disulfiram?

Cited by 42 publications

References 13 publications

Disulfiram and Copper Ions Kill Mycobacterium tuberculosis in a Synergistic Manner

Disulfiram and Copper Ions Kill Mycobacterium tuberculosis in a Synergistic Manner

Diethyldithiocarbamate complex with copper: the mechanism of action in cancer cells

PET Imaging Analysis with ⁶⁴Cu in Disulfiram Treatment for Aberrant Copper Biodistribution in Menkes Disease Mouse Model

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Bis-(diethyldithiocarbamato) copper complex: a new metabolite of disulfiram?

Cited by 42 publications

References 13 publications

Disulfiram and Copper Ions Kill Mycobacterium tuberculosis in a Synergistic Manner

Disulfiram and Copper Ions Kill Mycobacterium tuberculosis in a Synergistic Manner

Diethyldithiocarbamate complex with copper: the mechanism of action in cancer cells

PET Imaging Analysis with 64Cu in Disulfiram Treatment for Aberrant Copper Biodistribution in Menkes Disease Mouse Model

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PET Imaging Analysis with ⁶⁴Cu in Disulfiram Treatment for Aberrant Copper Biodistribution in Menkes Disease Mouse Model