- PII
- S30345278S0006302925050176-1
- DOI
- 10.7868/S3034527825050176
- Publication type
- Article
- Status
- Published
- Authors
- Volume/ Edition
- Volume 70 / Issue number 5
- Pages
- 1011-1021
- Abstract
- 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 B) causes stress in the endoplasmic reticulum, and the integrated stress leads to cell death by 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.
- Keywords
- дисульфирам диэтилдитиокарбамат клеточная гибель интегрированный ответ на стресс параптоз витамин В
- Date of publication
- 13.12.2025
- Year of publication
- 2025
- Number of purchasers
- 0
- Views
- 25
References
- 1. Weiser Drozdkova D. and Smesny Trtkova K. Possible therapeutic potential of disulfiram for multiple myeloma. Curr. Oncol., 28 (3), 2087–2096 (2021). DOI: 10.3390/curroncol28030193
- 2. Kannappan V., Ali M., Small B., Rajendran G., Elzhenni S., Taj H., Wang W., and Dou Q. P. Recent Advances in repurposing disulfiram and disulfiram derivatives as copper-dependent anticancer agents. Front. Mol. Biosci., 8, 741316 (2021). DOI: 10.3389/fmolb.2021.741316
- 3. Gan Y., Liu T., Feng W., Wang L., Li L. I., and Ning Y. Drug repositioning of disulfiram induces endometrioid epithelial ovarian cancer cell death via the both apoptosis and cuproptosis pathways. Oncol. Res., 31 (3), 333–343 (2023). DOI: 10.32604/or.2023.028694
- 4. Xu X., Han Y., Deng J., Wang S., Zhuo S., Zhao K., and Zhou W. Repurposing disulfiram with CuET nanocrystals: Enhancing anti-pyroptotic effect through NLRP3 inflammasome inhibition for treating inflammatory bowel diseases. Acta Pharmacol. Sin. B, 14 (6), 2698–2715 (2024). DOI: 10.1016/j.apsb.2024.03.003
- 5. Nechushtan H., Hamamreh Y., Nidal S., Gotfried M., Baron A., Shalev Y. I., Nisman B., Peretz T., and PeylanRamu N. A phase IIb trial assessing the addition of disulfiram to chemotherapy for the treatment of metastatic non-small cell lung cancer. Oncologist, 20 (4), 366–367 (2015). DOI: 10.1634/theoncologist.2014-0424
- 6. Lanz J., Biniaz-Harris N., Kuvaldina M., Jain S., Lewis K., and Fallon B. A. Disulfiram: Mechanisms, applications, and challenges. Antibiotics, 12 (3), (2023). DOI: 10.3390/antibiotics12030524
- 7. Kanellis D. C., Zisi A., and Skrott Z. Actionable cancer vulnerability due to translational arrest, p53 aggregation and ribosome biogenesis stress evoked by the disulfiram metabolite CuET. Cell Death Differ., 30 (7), 1666–1678 (2023). DOI: 10.1038/s41418-023-01167-4
- 8. Wu X., Xue X., Wang L., Wang W., Han J., Sun X., Zhang H., Liu Y., Che X., Yang J., and Wu C. Suppressing autophagy enhances disulfiram/copper-induced apoptosis in non-small cell lung cancer. Eur. J. Pharmacol., 827, 1–12 (2018). DOI: 10.1016/j.ejphar.2018.02.039
- 9. Ren L., Feng W., Shao J., Ma J., Xu M., Zhu B. Z., Zheng N., and Liu S. Diethyldithiocarbamate-copper nanocomplex reinforces disulfiram chemotherapeutic efficacy through light-triggered nuclear targeting. Theranostics, 10 (14), 6384–6398 (2020). DOI: 10.7150/thno.45558
- 10. Zhong S., Shengyu L., Xin S., Zhang X., Li K., Liu G., Li L., Tao S., Zheng B., Sheng W., Ye Z., Xing Q., Zhai Q., Ren L., Wu Y., and Bao Y. Disulfiram in glioma: Literature review of drug repurposing. Front. Pharmacol., 13, 933655 (2022). DOI: 10.3389/fphar.2022.933655
- 11. Nobel C. I., Kimland M., Lind B., Orrenius S., and Slater A. F. Dithiocarbamates induce apoptosis in thymocytes by raising the intracellular level of redox-active copper. J. Biol. Chem., 270 (44), 26202–26208 (1995). DOI: 10.1074/jbc.270.44.26202
- 12. Mays D. C., Nelson A. N., Lam-Holt J., Fauq A. H., and Lipsky J. J. S-methyl-N,N-diethylthiocarbamate sulfoxide and S-methyl-N,N-diethylthiocarbamate sulfone, two candidates for the active metabolite of disulfiram. Alcohol.: Clin. Exp. Res., 20 (3), 595–600 (1996). DOI: 10.1111/j.1530-0277.1996.tb01099.x
- 13. Lipsky J. J., Shen M. L., and Naylor S. Overview – in vitro inhibition of aldehyde dehydrogenase by disulfiram and metabolites. Chem. Biol. Interact., 130–132 (1–3), 81–91 (2001). DOI: 10.1016/s0009-2797(00)00224-6
- 14. Ningaraj N. S., Schloss J. V., Williams T. D., and Faiman M. D. Glutathione carbamoylation with S-methyl N,N-diethylthiolcarbamate sulfoxide and sulfone. Mitochondrial low Km aldehyde dehydrogenase inhibition and implications for its alcohol-deterrent action. Biochem. Pharmacol., 55 (6), 749–756 (1998). DOI: 10.1016/s0006-2952(97)00513-3
- 15. Solovieva M. E., Shatalin Y. V., Solovyev V. V., Sazonov A. V., Kutyshenko V. P., and Akatov V. S. Hydroxycobalamin catalyzes the oxidation of diethyldithiocarbamate and increases its cytotoxicity independently of copper ions. Redox Biol., 20, 28–37 (2019). DOI: 10.1016/j.redox.2018.09.016
- 16. Solovieva M., Shatalin Y., Fadeev R., Krestinina O., Baburina Y., Kruglov A., Kharechkina E., Kobyakova M., Rogachevsky V., Shishkova E., and Akatov A. V. Vitamin B enhances the cytotoxicity of diethyldithiocarbamate in a synergistic manner, inducing the paraptosis-like death of human Larynx carcinoma cells. Biomolecules, 10 (1), (2020). DOI: 10.3390/biom10010069
- 17. Solovieva M., Shatalin Y., Odinokova I., Krestinina O., Baburina Y., Mishukov A., Lomovskaya Y., Pavlik L., Mikheeva I., Holmuhamedov E., and Akatov V. Disulfiram oxy-derivatives induce entosis or paraptosis-like death in breast cancer MCF-7 cells depending on the duration of treatment. Biochim. Biophys. Acta. Gen. Subj., 1866 (9), 130184 (2022). DOI: 10.1016/j.bbagen.2022.130184
- 18. Dumay A., Rincheval V., Trotot P., Mignotte B., and Vayssière J. L. The superoxide dismutase inhibitor diethyldithiocarbamate has antagonistic effects on apoptosis by triggering both cytochrome c release and caspase inhibition. Free Rad. Biol. Med., 40 (8), 1377–1390 (2006). DOI: 10.1016/j.freeradbiomed.2005.12.005
- 19. Park S. S., Lee D. M., Lim J. H., Lee D., Park S. J., Kim H. M., Sohn S., Yoon G., Eom Y. W., Jeong S. Y., Choi E. K., and Choi K. S. Pyrrolidine dithiocarbamate reverses Bcl-xL-mediated apoptotic resistance to doxorubicin by inducing paraptosis. Carcinogenesis, 39 (3), 458–470 (2018). DOI: 10.1093/carcin/bgy003
- 20. Qiu C., Zhang X., Huang B., Wang S., Zhou W., Li C., Li X., Wang J., and Yang N. Disulfiram, a ferroptosis inducer, triggers lysosomal membrane permeabilization by up-regulating ROS in glioblastoma. Onco Targets Ther., 13, 10631–10640 (2020). DOI: 10.2147/ott.s272312
- 21. Tsvetkov P. and Coy S. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science, 375 (6586), 1254–1261 (2022). DOI: 10.1126/science.abf0529
- 22. Gao X., Huang H., Pan C., and Mei Z. Disulfiram/copper induces immunogenic cell death and enhances CD47 blockade in hepatocellular carcinoma. Cancers, 14 (19), (2022). DOI: 10.3390/cancers14194715
- 23. Tardito S., Bassanetti I., Bignardi C., Elviri L., Tegoni M., Mucchino C., Bussolati O., Franchi-Gazzola R., and Marchiò L. Copper binding agents acting as copper ionophores lead to caspase inhibition and paraptotic cell death in human cancer cells. J. Am. Chem. Soc., 133 (16), 6235–6242 (2011). DOI: 10.1021/ja109413c
- 24. Sperandio S., Poksay K., de Belle I., Lafuente M. J., Liu B., Nasir J., and Bredesen D. E. Paraptosis: mediation by MAP kinases and inhibition by AIP-1/Alix. Cell Death Differ., 11 (10), 1066–1075 (2004). DOI: 10.1038/sj.cdd.4401465
- 25. Hanson S., Dharan A., P V J., Pal S., Nair B. G., Kar R., and Mishra N. Paraptosis: a unique cell death mode for targeting cancer. Front. Pharmacol., 14, 1159409 (2023). DOI: 10.3389/fphar.2023.1159409
- 26. Monel B., Compton A. A., Bruel T., Amraoui S., Burlaud-Gaillard J., Roy N., Guivel-Benhassine F., Porrot F., Génin P., Meertens L., Sinigaglia L., Jouvenet N., Weil R., Casartelli N., Demangel C., Simon-Lorière E., Moris A., Roingeard P., Amara A., and Schwartz O. Zika virus induces massive cytoplasmic vacuolization and paraptosis-like death in infected cells. EMBO J., 36 (12), 1653–1668 (2017). DOI: 10.15252/embj.201695597
- 27. Huang X., Huang Y., Yang Y., Wei S., and Qin Q. Involvement of fish signal transducer and activator of transcription 3 (STAT3) in SGIV replication and virus induced paraptosis. Fish Shellfish Immunol., 41 (2), 308–316 (2014). DOI: 10.1016/j.fsi.2014.09.011
- 28. Pyrczak-Felczykowska A., Reekie T. A., Jąkalski M., Hać A., Malinowska M., Pawlik A., Ryś K., GuzowKrzemińska B., and Herman-Antosiewicz A. The isoxazole derivative of usnic acid induces an ER stress response in breast cancer cells that leads to paraptosis-like cell death. Int. J. Mol. Sci., 23 (3), 1802 (2022). DOI: 10.3390/ijms23031802
- 29. Wang X., Hua P., He C., and Chen M. Non-apoptotic cell death-based cancer therapy: Molecular mechanism, pharmacological modulators, and nanomedicine. Acta Pharmacol. Sin. B, 12 (9), 3567–3593 (2022). DOI: 10.1016/j.apsb.2022.03.020
- 30. Lee H. J., Lee D. M., Seo M. J., Kang H. C., Kwon S. K., and Choi K. S. PSMD14 targeting triggers paraptosis in breast cancer cells by inducing proteasome inhibition and Ca imbalance. Int. J. Mol. Sci., 23 (5), 2648 (2022). DOI: 10.3390/ijms23052648
- 31. Mandula J. K., Chang S., Mohamed E., Jimenez R., Sierra-Mondragon R. A., Chang D. C., Obermayer A. N., Moran-Segura C. M., Das S., Vazquez-Martinez J. A., Prieto K., Chen A., Smalley K. S. M., Czerniecki B., Forsyth P., Koya R. C., Ruffell B., Cubillos-Ruiz J. R., Munn D. H., Shaw T. I., Conejo-Garcia J. R., and Rodriguez P. C. Ablation of the endoplasmic reticulum stress kinase PERK induces paraptosis and type I interferon to promote anti-tumor T cell responses. Cancer Cell, 40 (10), 1145–1160.e1149 (2022). DOI: 10.1016/j.ccell.2022.08.016
- 32. Park W., Wei S., Kim B.-S., Kim B., Bae S.-J., Chae Y. C., Ryu D., and Ha K.-T. Diversity and complexity of cell death: a historical review. Exp. Mol. Med., 55 (8), 1573–1594 (2023). DOI: 10.1038/s12276-023-01078-x
- 33. Schindelin J., Arganda-Carreras I., Frise E., Kaynig V., Longair M., Pietzsch T., Preibisch S., Rueden C., Saalfeld S., Schmid B., Tinevez J. Y., White D. J., Hartenstein V., Eliceiri K., Tomancak P., and Cardona A. Fiji: an open-source platform for biological-image analysis. Nat. Methods, 9 (7), 676–682 (2012). DOI: 10.1038/nmeth.2019.
- 34. Sauler M., Bazan I. S., and Lee P. J. Cell death in the lung: The apoptosis-necroptosis axis. Ann. Rev. Physiol., 81, 375–402 (2019). DOI: 10.1146/annurev-physiol-020518-114320
- 35. Grignano E., Birsen R., Chapuis N., and Bouscary D. From iron chelation to overload as a therapeutic strategy to induce ferroptosis in leukemic cells. Front. Oncol., 10, 586530 (2020). DOI: 10.3389/fonc.2020.586530
- 36. Dixon S. J., Lemberg K. M., Lamprecht M. R., Skouta R., Zaitsev E. M., Gleason C. E., Patel D. N., Bauer A. J., Cantley A. M., Yang W. S., Morrison B., and Stockwell B. R. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell, 149 (5), 1060–1072 (2012). DOI: 10.1016/j.cell.2012.03.042
- 37. Solovieva M., Shatalin Y., Odinokova I., Krestinina O., Baburina Y., Lomovskaya Y., Pankratov A., Pankratova N., Buneeva O., Kopylov A., Medvedev A., and Akatov V. Disulfiram oxy-derivatives suppress protein retrotranslocation across the er membrane to the cytosol and initiate paraptosis-like cell death. Membranes, 12 (9), 845 (2022). DOI: 10.3390/membranes12090845
- 38. Liu Y., Shoji-Kawata S., Sumpter R. M. Jr., Wei Y., Ginet V., Zhang L., Posner B., Tran K. A., Green D. R., Xavier R. J., Shaw S. Y., Clarke P. G., Puyal J., and Levine B. Autosis is a Na,K-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia. Proc. Natl. Acad. Sci. USA, 110 (51), 20364–20371 (2013). DOI: 10.1073/pnas.1319661110
- 39. Pakos-Zebrucka K., Koryga I., Mnich K., Ljujic M., and Samali A. The integrated stress response. EMBO Rep., 17 (10), 1374–1395 (2016). DOI: 10.15252/embr.201642195
- 40. Kalinin A., Zubkova E., and Menshikov M. Integrated stress response (ISR) pathway: unraveling its role in cellular senescence. Int. J. Mol. Sci., 24 (24), 17423 (2023). DOI: 10.3390/ijms242417423
- 41. Lu H. J., Koju N., and Sheng R. Mammalian integrated stress responses in stressed organelles and their functions. Acta Pharmacol. Sin., 45 (6), 1095–1114 (2024). DOI: 10.1038/s41401-023-01225-0
- 42. Oyadomari S. and Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ., 11 (4), 381–389 (2004). DOI: 10.1038/sj.cdd.4401373
- 43. Wang Z., Jiang H., Cai L. Y., Ji N., and Zeng X. Repurposing disulfiram to induce OSCC cell death by cristae dysfunction promoted autophagy. Oral Dis., 27 (5), 1148–1160 (2021). DOI: 10.1111/odi.13652
- 44. Zhang J., Gao R. F., Li J., Yu K. D., and Bi K. X. Alloimperatorin activates apoptosis, ferroptosis, and oxeiptosis to inhibit the growth and invasion of breast cancer cells in vitro. Biochem. Cell Biol., 100 (3), 213–222 (2022). DOI: 10.1139/bcb-2021-0399
- 45. Соловьева М. Е., Шаталин Ю. В. и Акатов В. С. Параптоз и другие типы неапоптотической регулируемой гибели клеток. Биофизика, 69 (4), 786–804 (2024). DOI: 10.31857/s0006302924040117
- 46. Zwerger M., Kolb T., Richter K., Karakesisoglou I., and Herrmann H. Induction of a massive endoplasmic reticulum and perinuclear space expansion by expression of lamin B receptor mutants and the related sterol reductases TM7SF2 and DHCR7. Mol. Biol. Cell, 21 (2), 354–368 (2010). DOI: 10.1091/mbc.e09-08-0739.
- 47. Lukášová E., Kovařík A., and Kozubek S. Consequences of Lamin B1 and Lamin B receptor downregulation in senescence. Cells, 7 (2), (2018). DOI: 10.3390/cells7020011
- 48. Kobyakova M., Lomovskaya Y., Senotov A., Lomovsky A., Minaychev V., Fadeeva I., Shtatnova D., Krasnov K., Zvyagina A., Odinokova I., Akatov V., and Fadeev R. The increase in the drug resistance of acute myeloid leukemia THP-1 cells in high-density cell culture is associated with inflammatory-like activation and antiapoptotic Bcl-2 proteins. Int. J. Mol. Sci., 23 (14) (2022). DOI: 10.3390/ijms23147881
- 49. Sun Q., Chen T., Wang X., and Wei X. Taxol induces paraptosis independent of both protein synthesis and MAPK pathway. J. Cell. Physiol., 222 (2), 421–432 (2010). DOI: 10.1002/jcp.21982
- 50. Wang L., Gundelach J. H., and Bram R. J. Cycloheximide promotes paraptosis induced by inhibition of cyclophilins in glioblastoma multiforme. Cell Death Dis., 8 (5), e2807 (2017). DOI: 10.1038/cddis.2017.217