Oxidized Disulfiram Derivatives Activate an Integrated Stress Response and Cause Paraptosis of Human Cancer Cells BT474
M. E. SolovievaInstitute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290, Pushchino, Moscow oblast, RussiaI. V. OdinokovaInstitute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290, Pushchino, Moscow oblast, RussiaYu. V. ShatalinCenter for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, 119334, Moscow, RussiaA. A. MishukovCenter for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, 119334, Moscow, RussiaE. L. HolmuhamedovInstitute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290, Pushchino, Moscow oblast, RussiaV. S. AkatovInstitute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290, Pushchino, Moscow oblast, Russia
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Disulfiram, a well-known anti-alcohol drug with minimal side effects, as well as other dithiocarbamates are being investigated as part of the “Drug repurposing” program in order to expand their use, including in oncology. In this work, using the example of human tumor cells BT474, it was found that the action of oxidized disulfiram metabolites generated by aerobic oxidation of diethyldithiocarbamate in the presence of the catalyst cobalamin (vitamin B12b) causes stress in the endoplasmic reticulum, and the integrated response to stress leads to cell death through paraptosis. The ability of substances of this class to cause non-apoptotic types of cell death is of interest for the development of new approaches in oncotherapy.
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