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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

Effects of disulfiram and copper supplementation on cell viability of ovarian cancer cellsSix ovarian cancer cell lines were treated for 72 h with 0-5 μM disulfiram (DSF) in the absence or presence of 1 μM copper chloride (Cu2+) and analyzed for cell viability by the MTT assay.
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Figure 1: Effects of disulfiram and copper supplementation on cell viability of ovarian cancer cellsSix ovarian cancer cell lines were treated for 72 h with 0-5 μM disulfiram (DSF) in the absence or presence of 1 μM copper chloride (Cu2+) and analyzed for cell viability by the MTT assay.

Mentions: Six ovarian cancer cell lines were tested for their sensitivity to disulfiram either as a single agent or in combination with copper chloride. In the absence of copper supplementation, disulfiram exhibited a characteristic bi-phasic dose-response curve, reducing cell survival of ovarian cancer cells at an optimum concentration of around 1 – 2 μM disulfiram (Fig. 1). Notably, the OVMZ-31 cell line proved to be poorly sensitive to disulfiram treatment, whereas the OVMZ-37 cell line responded well to disulfiram even in the absence of additional copper supplementation. Supplementation with 1 μM copper chloride, however, increased the cytotoxic effect of disulfiram in all other ovarian cancer cells tested.


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)

Effects of disulfiram and copper supplementation on cell viability of ovarian cancer cellsSix ovarian cancer cell lines were treated for 72 h with 0-5 μM disulfiram (DSF) in the absence or presence of 1 μM copper chloride (Cu2+) and analyzed for cell viability by the MTT assay.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Effects of disulfiram and copper supplementation on cell viability of ovarian cancer cellsSix ovarian cancer cell lines were treated for 72 h with 0-5 μM disulfiram (DSF) in the absence or presence of 1 μM copper chloride (Cu2+) and analyzed for cell viability by the MTT assay.
Mentions: Six ovarian cancer cell lines were tested for their sensitivity to disulfiram either as a single agent or in combination with copper chloride. In the absence of copper supplementation, disulfiram exhibited a characteristic bi-phasic dose-response curve, reducing cell survival of ovarian cancer cells at an optimum concentration of around 1 – 2 μM disulfiram (Fig. 1). Notably, the OVMZ-31 cell line proved to be poorly sensitive to disulfiram treatment, whereas the OVMZ-37 cell line responded well to disulfiram even in the absence of additional copper supplementation. Supplementation with 1 μM copper chloride, however, increased the cytotoxic effect of disulfiram in all other ovarian cancer cells tested.

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