Tamoxifen inhibits mitochondrial membrane damage caused by disulfiram

Pavón, Natalia; Buelna‐Chontal, Mabel; Correa, Francisco; Yoval-Sánchez, Belem; Belmont, Javier; Hernández‐Esquivel, Luz; Rodríguez‐Zavala, José S.; Chávez, Edmundo

doi:10.1139/bcb-2017-0027

Cited by 6 publications

(2 citation statements)

References 29 publications

(23 reference statements)

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“…Moreover, the proteolytic fragments produced by cleavage of mutant ataxin-3 lead to nuclear translocation of ataxin-3 and cell death. In addition, it has been reported that disulfiram induces oxidative stress (Grosicka-Maciąg et al, 2010;Pavón et al, 2017). Oxidative stress has also been characterized as an inducer of nuclear ataxin-3 transport (Reina et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…The most adverse effect of disulfiram treatment is neurotoxicity, including neurofilamentous distal axonopathy, sensorimotor polyneuropathy and peripheral neuropathy in human patients and experimental animal models (Kulkarni et al, 2013;Stone et al, 2014). In addition, disulfiram can cause mitochondrial membrane damage (Pavón et al, 2017). Interestingly, one of the pathogenic mechanisms of SCA3 is mitochondrial dysfunction (Duarte-Silva et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Disulfiram facilitates ataxin-3 nuclear translocation and potentiates the cytotoxicity in a cell model of SCA3

Wang

2019

J. Toxicol. Sci.

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Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of a glutamine-encoding CAG repeat in the ATXN3 gene encoding the protein ataxin-3. The nuclear presence of polyglutamineexpanded ataxin-3 is of critical importance for the pathogenesis of SCA3. Disulfiram, an FDA-approved drug for alcoholism, has also garnered attention in cancer treatment. However, it has shown toxicity in the nervous system. Bearing this in mind, we treated cells expressing ataxin-3 with disulfiram to measure several pathogenic cascades of SCA3, including aggregate formation, soluble ataxin-3 expression and nuclear localization of ataxin-3 and the cytotoxicity, which assess the direct effect of disulfiram on SCA3 cell models. To our knowledge, this is direct evidence that disulfiram elevated the nuclear localization of polyglutamine-expanded ataxin-3 and enhanced the cytotoxicity in a cell model of SCA3. Furthermore, disulfiram did not affect the aggregate formation of polyglutamine-expanded ataxin-3 at least at a single dose. Our findings repurpose disulfiram as a modulator of ataxin-3 nuclear transport that aggravates the pathology of SCA3, which is a new target for disulfiram. This study also represents an important example of determining novel side effects in pre-existing drugs. This study suggests that caution may be warranted when this compound is used to treat alcohol abuse or cancer in patients carrying a SCA3-causing mutation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Disulfiram facilitates ataxin-3 nuclear translocation and potentiates the cytotoxicity in a cell model of SCA3

Wang

2019

J. Toxicol. Sci.

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Calcium Induces Mitochondrial Oxidative Stress Because of its Binding to Adenine Nucleotide Translocase

Correa

Pavón

Buelna‐Chontal

et al. 2018

Cell Biochem Biophys

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Several studies have demonstrated that the mitochondrial membrane switches from selective to non-selective permeability because of its improved matrix Ca accumulation and oxidative stress. This process, known as permeability transition, evokes severe dysfunction in mitochondria through the opening of a non-specific pore, whose chemical nature is still under discussion. There are some proposals regarding the components of the pore structure, e.g., the adenine nucleotide translocase and dimers of the F1 Fo-ATP synthase. Our results reveal that Ca induces oxidative stress, which not only increases lipid peroxidation and ROS generation but also brings about both the collapse of the transmembrane potential and the membrane release of cytochrome c. Additionally, it is shown that Ca increases the binding of the probe eosin-5-maleimide to adenine nucleotide translocase. Interestingly, these effects are diminished after the addition of ADP. It is suggested that pore opening is caused by the binding of Ca to the adenine nucleotide translocase.

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Triphenylethylene analogues: Design, synthesis and evaluation of antitumor activity and topoisomerase inhibitors

Rani

Paul

2020

European Journal of Medicinal Chemistry

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Tamoxifen inhibits mitochondrial membrane damage caused by disulfiram

Cited by 6 publications

References 29 publications

Disulfiram facilitates ataxin-3 nuclear translocation and potentiates the cytotoxicity in a cell model of SCA3

Disulfiram facilitates ataxin-3 nuclear translocation and potentiates the cytotoxicity in a cell model of SCA3

Calcium Induces Mitochondrial Oxidative Stress Because of its Binding to Adenine Nucleotide Translocase

Triphenylethylene analogues: Design, synthesis and evaluation of antitumor activity and topoisomerase inhibitors

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