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Disulfiram/copper causes redox-related proteotoxicity and concomitant heat shock response in ovarian cancer cells that is augmented by auranofin-mediated thioredoxin inhibition.

Papaioannou M, Mylonas I, Kast RE, Brüning A - Oncoscience (2013)

Bottom Line: Within few hours of application, disulfiram caused irreversible cell damage associated with pronounced induction of the inducible heat shock proteins HSP70, HSP40, and HSP32.The small heat shock protein HSP27 was found to be covalently dimerized via oxidized disulfide bonds and precipitated in para-nuclear protein aggregates.Simultaneous inhibition of the cellular thioredoxin system by auranofin further enhanced the cytotoxic effect of disulfiram.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics/Gynecology, University Hospital Munich, Germany.

ABSTRACT
A valuable strategy to develop new therapeutic options for a variety of diseases has been the identification of new targets and applications for already approved drugs, the so-called drug repositioning. Recurrent ovarian cancer is a nearly incurable malignancy for which new and effective treatments are urgently needed. The alcohol-deterring drug disulfiram has been shown to cause preferential cell death in a variety of cancer cells. In this study, it is shown that disulfiram mediates effective cell death in ovarian cancer cells by promoting a pro-oxidative intracellular environment in a copper-dependent mechanism. Within few hours of application, disulfiram caused irreversible cell damage associated with pronounced induction of the inducible heat shock proteins HSP70, HSP40, and HSP32. The small heat shock protein HSP27 was found to be covalently dimerized via oxidized disulfide bonds and precipitated in para-nuclear protein aggregates. Simultaneous inhibition of the cellular thioredoxin system by auranofin further enhanced the cytotoxic effect of disulfiram. These data indeed indicate that the combination of two approved drugs, the anti-alcoholic disulfiram and the anti-rheumatic auranofin, may be of interest for the treatment of recurrent and genotoxic drug-resistant ovarian cancer by inducing a proteotoxic cell death mechanism.

No MeSH data available.


Related in: MedlinePlus

Auranofin enhances the cytotoxic effect of disulfiram/copperA) OVCAR3 cells were treated for 72 h with the indicated low concentrations of disulfiram/copper (equal molar ratios each) in the absence (rhombus) or presence (rectangles) of 1 μM auranofin. B) OVCAR3 cells treated for 24 h with either 1 μM auranofin (AUR), 250 nM disulfiram/copper (DSF/Cu), or a combination of both (TRIPLE) were subjected to Western blot analysis of the indicated proteins under non-reducing conditions.
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Figure 7: Auranofin enhances the cytotoxic effect of disulfiram/copperA) OVCAR3 cells were treated for 72 h with the indicated low concentrations of disulfiram/copper (equal molar ratios each) in the absence (rhombus) or presence (rectangles) of 1 μM auranofin. B) OVCAR3 cells treated for 24 h with either 1 μM auranofin (AUR), 250 nM disulfiram/copper (DSF/Cu), or a combination of both (TRIPLE) were subjected to Western blot analysis of the indicated proteins under non-reducing conditions.

Mentions: To protect and recover from cytotoxic protein thiol oxidation, cells have developed the thioredoxin/thioredoxin reductase system [17]. Auranofin is an anti-rheumatic drug that has also been shown to inhibit functional activity of the thioredoxin reductase. This had led to the proposal that auranofin could enhance the anti-cancer effect of reactive oxygen species-inducing drugs, including that of disulfiram/copper [9]. In fact, co-administration of auranofin enhanced the cytotoxic effect of low disulfiram/copper concentrations on ovarian cancer cells as shown by MTT assay analysis (Fig. 7A) and clonal assay analysis (Fig. 7B). Western blot analysis revealed that in particular the oxidation and dimerization of HSP27 was enhanced by additional application of auranofin to disulfiram/copper.


Disulfiram/copper causes redox-related proteotoxicity and concomitant heat shock response in ovarian cancer cells that is augmented by auranofin-mediated thioredoxin inhibition.

Papaioannou M, Mylonas I, Kast RE, Brüning A - Oncoscience (2013)

Auranofin enhances the cytotoxic effect of disulfiram/copperA) OVCAR3 cells were treated for 72 h with the indicated low concentrations of disulfiram/copper (equal molar ratios each) in the absence (rhombus) or presence (rectangles) of 1 μM auranofin. B) OVCAR3 cells treated for 24 h with either 1 μM auranofin (AUR), 250 nM disulfiram/copper (DSF/Cu), or a combination of both (TRIPLE) were subjected to Western blot analysis of the indicated proteins under non-reducing conditions.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4295765&req=5

Figure 7: Auranofin enhances the cytotoxic effect of disulfiram/copperA) OVCAR3 cells were treated for 72 h with the indicated low concentrations of disulfiram/copper (equal molar ratios each) in the absence (rhombus) or presence (rectangles) of 1 μM auranofin. B) OVCAR3 cells treated for 24 h with either 1 μM auranofin (AUR), 250 nM disulfiram/copper (DSF/Cu), or a combination of both (TRIPLE) were subjected to Western blot analysis of the indicated proteins under non-reducing conditions.
Mentions: To protect and recover from cytotoxic protein thiol oxidation, cells have developed the thioredoxin/thioredoxin reductase system [17]. Auranofin is an anti-rheumatic drug that has also been shown to inhibit functional activity of the thioredoxin reductase. This had led to the proposal that auranofin could enhance the anti-cancer effect of reactive oxygen species-inducing drugs, including that of disulfiram/copper [9]. In fact, co-administration of auranofin enhanced the cytotoxic effect of low disulfiram/copper concentrations on ovarian cancer cells as shown by MTT assay analysis (Fig. 7A) and clonal assay analysis (Fig. 7B). Western blot analysis revealed that in particular the oxidation and dimerization of HSP27 was enhanced by additional application of auranofin to disulfiram/copper.

Bottom Line: Within few hours of application, disulfiram caused irreversible cell damage associated with pronounced induction of the inducible heat shock proteins HSP70, HSP40, and HSP32.The small heat shock protein HSP27 was found to be covalently dimerized via oxidized disulfide bonds and precipitated in para-nuclear protein aggregates.Simultaneous inhibition of the cellular thioredoxin system by auranofin further enhanced the cytotoxic effect of disulfiram.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics/Gynecology, University Hospital Munich, Germany.

ABSTRACT
A valuable strategy to develop new therapeutic options for a variety of diseases has been the identification of new targets and applications for already approved drugs, the so-called drug repositioning. Recurrent ovarian cancer is a nearly incurable malignancy for which new and effective treatments are urgently needed. The alcohol-deterring drug disulfiram has been shown to cause preferential cell death in a variety of cancer cells. In this study, it is shown that disulfiram mediates effective cell death in ovarian cancer cells by promoting a pro-oxidative intracellular environment in a copper-dependent mechanism. Within few hours of application, disulfiram caused irreversible cell damage associated with pronounced induction of the inducible heat shock proteins HSP70, HSP40, and HSP32. The small heat shock protein HSP27 was found to be covalently dimerized via oxidized disulfide bonds and precipitated in para-nuclear protein aggregates. Simultaneous inhibition of the cellular thioredoxin system by auranofin further enhanced the cytotoxic effect of disulfiram. These data indeed indicate that the combination of two approved drugs, the anti-alcoholic disulfiram and the anti-rheumatic auranofin, may be of interest for the treatment of recurrent and genotoxic drug-resistant ovarian cancer by inducing a proteotoxic cell death mechanism.

No MeSH data available.


Related in: MedlinePlus