Disulfiram and the challenges of modern medicine – new directions and possibilities
DOI:
https://doi.org/10.12923/cipms-2026-0020Keywords:
disulfiram, breast cancer, pancreatic cancer, glioma, HIV, COVID-19Abstract
Disulfiram, originally developed for the treatment of alcohol dependence, has recently gained attention for its potential applications in oncology and infectious diseases. In breast and pancreatic cancers, disulfiram forms copper complexes that inhibit tumor growth, induce oxidative stress, and enhance the efficacy of chemotherapy and radiotherapy. It targets cancer stem cells and modulates key enzymes such as aldehyde dehydrogenase (ALDH) and O6-methylguanine-DNA methyltransferase (MGMT), thereby increasing tumor sensitivity to agents such as gemcitabine and temozolomide. In glioblastoma, disulfiram also inhibits polo-like kinase 1 and proteasome activity, promoting apoptosis.
In HIV therapy, disulfiram contributes to the “shock-and-kill” strategy by reactivating latent viral reservoirs without significant immune activation. In COVID-19, it may inhibit viral proteases (Mpro, PLpro) and reduce neutrophil extracellular trap (NET) formation, potentially mitigating disease severity. Observational studies suggest a reduced risk of infection and symptom development among disulfiram users. Beyond these areas, disulfiram has demonstrated in vitro activity against a broad spectrum of pathogens, including Borrelia burgdorferi, vancomycin-resistant bacteria, hepatitis C virus, and various parasites. It has also been explored as an adjunct in the treatment of cocaine dependence. Although most findings remain preclinical, the breadth of disulfiram’s biological activity supports continued investigation into its therapeutic potential across diverse medical domains.
References
1. Dosset M, Zanetti M. Disulfiram’s journey from rubber vulcaniza-tion to T cell activation. EMBO J. 2022;41:e111862. https://doi.org/10.15252/embj.2022111862.
2. Kragh H. From disulfiram to Antabuse: the invention of a drug. Bull Hist Chem. 2008;33(2):82‑8.
3. Lanz J, Biniaz Harris N, Kuvaldina M, Ma J, Harrison D, Smith R, et al. Disulfiram: mechanisms, applications, and challenges. Antibiotics. 2023;12:524. https://doi.org/10.3390/antibiotics12030524.
4. Pattanayak R, Sagar R, Pal A. Tracing the journey of disulfiram: from an unintended discovery to a treatment option for alcoholism. J Ment Health Hum Behav. 2015;20:41.
5. Stokłosa I, Więckiewicz G, Stokłosa M, Ziółkowski M, Wnuk K, Sieradzka A, et al. Medications for the treatment of alcohol dependence – current state of knowledge and future perspectives. Int J Environ Res Public Health. 2023;20:1870. https://doi.org/10.3390/ijerph20031870.
6. MedlinePlus. Disulfiram: drug information. U.S. National Library of Medicine. Available from: https://medlineplus.gov/druginfo/meds/a682602.html. Accessed 2025 May 20.
7. Charakterystyka Produktu Leczniczego Anticol. Available from: https://rejestry.ezdrowie.gov.pl/medicinal-products/600/characteristic. Accessed 2025 May 8.
8. Skinner MD, Lahmek P, Pham H, Aubin HJ, Reynaud M, Luquiens A, et al. Disulfiram efficacy in the treatment of alcohol dependence: a meta-analysis. PLoS One. 2014;9:e87366. https://doi.org/10.1371/journal.pone.0087366.
9. Charakterystyka Produktu Leczniczego Disulfiram WZF. Available from: https://rejestry.ezdrowie.gov.pl/medicinal-products/1971/characteristic. Accessed 2025 May 8.
10. Axelrath S. Disulfiram should remain second-line treatment for most patients with alcohol use disorder. J Addict Med. 2024;18(6):617‑8. https://doi.org/10.1097/ADM.0000000000001360.
11. Pogoda K, Niwińska A, Jagiełło‑Gruszfeld A, Staniunas R, Pieńkowski T, Jassem J, et al. Breast cancer in young women. Oncol Clin Pract. 2015;11:276‑91.
12. Skrott Z, Mistrik M, Andersen KK, Friis S, Majera D, Gursky J, et al. Alcohol abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature. 2017;552:194‑9. https://doi.org/10.1038/nature25016.
13. Wang R, Shen J, Yan H, Li H, Wang X, Zhang L, et al. The evolving role of disulfiram in radiobiology and the treatment of breast cancer. Onco Targets Ther. 2020;13:10441‑6. https://doi.org/10.2147/OTT.S271532.
14. Sun T, Yang W, Toprani SM, Wang G, Luo J, Hu L, et al. Induction of immunogenic cell death in radiation‑resistant breast cancer stem cells by repurposing disulfiram. Cell Commun Signal. 2020;18:36. https://doi.org/10.1186/s12964-019-0507-3.
15. Yang Z, Guo F, Albers AE, Sehouli J, Kaufmann A, Eberhardt A, et al. Disulfiram modulates ROS accumulation and overcomes synergistically cisplatin resistance in breast cancer cell lines. Biomed Pharmacother. 2019;113:108727. https://doi.org/10.1016/j.biopha.2019.108727.
16. Rebelo R, Polónia B, Santos LL, Gonçalves AC, Almeida AM, Coelho R, et al. Drug repurposing opportunities in pancreatic ductal adenocarcinoma. Pharmaceuticals. 2021;14:280. https://doi.org/10.3390/ph14030280.
17. Wang Y, Zhou Q, Luo W, Zhang K, Li J, Chen S, et al. Collagenase decorated copper nanotheranostics for optimizing cuproptosis and MRI in pancreatic ductal adenocarcinoma. J Nanobiotechnology. 2024;22:689. https://doi.org/10.1186/s12951-024-02968-6.
18. Huang S, Xie P, Huang X, Zheng Y, Li M, Song H, et al. Disulfiram combined with chemoimmunotherapy potentiates pancreatic cancer treatment via cGAS‑STING pathway activation. Am J Cancer Res. 2023;13:2055‑65. PMID:37293156.
19. Zhang X, Hu P, Ding SY, Sun T, Liu L, Han S, et al. Induction of autophagy‑dependent apoptosis in cancer cells through activation of ER stress. Am J Cancer Res. 2019;9:1266‑81. PMID:31285958; PMCID:PMC6610050.
20. Li Z, Xie X, Tan G, Zhang W, Jiang Y, Wang Y, et al. Disulfiram synergizes with SRC inhibitors to suppress pancreatic cancer growth. Biol Pharm Bull. 2021;44:1323‑31. https://doi.org/10.1248/bpb.b21-00353.
21. Bubin R, Uljanovs R, Strumfa I. Cancer stem cells in pancreatic ductal adenocarcinoma. Int J Mol Sci. 2023;24:7030. https://doi.org/10.3390/ijms24087030.
22. Kim SK, Kim H, Lee D, Kim YH, Jeong J, Park S, et al. Targeting ALDHhigh therapy‑resistant pancreatic cancer cells. PLoS One. 2013;8(10):e78130. https://doi.org/10.1371/journal.pone.0078130.
23. Xu Y, Lu L, Luo J, Zhang B, Cheng Y, Chen J, et al. Disulfiram as radiosensitizer for pancreatic cancer. Front Oncol. 2021;11:683695. https://doi.org/10.3389/fonc.2021.683695.
24. Cong J, Wang Y, Zhang X, Zhang N, Zhou B, Hu H, et al. Chemoradiation targeting stem and non‑stem pancreatic cancer cells by disulfiram. Cancer Lett. 2017;409:9‑19. https://doi.org/10.1016/j.canlet.2017.08.028.
25. Wang Y, Drum DL, Sun R, Li P, Chen X, Ling X, et al. Cancer cell stress drives reprogramming of CAR T cells. Nat Commun. 2023;14:5727. https://doi.org/10.1038/s41467-023-41282-x.
26. Kelley KC, Grossman KF, Brittain Blankenship M, McClellan S, Akhtar S, White TF, et al. Phase I study of disulfiram and copper gluconate using S‑glutathionylation as a biomarker. BMC Cancer. 2021;21:510. https://doi.org/10.1186/s12885-021-08242-4.
27. ClinicalTrials.gov. Study NCT02671890: Disulfiram and chemo-therapy in refractory solid tumors. Available from: https://clinicaltrials.gov/study/NCT02671890. Accessed 2025 May 16.
28. Zhong S, Liu S, Shi X, Liu Y, Sun Y, Zhao J, et al. Disulfiram in glioma: drug repurposing review. Front Pharmacol. 2022;13:933655. https://doi.org/10.3389/fphar.2022.933655.
29. White J, White MPJ, Wickremesekera A, Marsh R, Finlayson M, Sinks D, et al. Tumor micro‑environment and recurrence in glioblastoma. J Transl Med. 2024;22:540. https://doi.org/10.1186/s12967 -024-05301-9.
30. Zhao Y, Xiao Z, Chen W, Wei Z, Chen Y, Liu J, et al. Disulfiram sensitizes pituitary adenoma to temozolomide. Mol Med Rep. 2015;12:2313‑22. https://doi.org/10.3892/mmr.2015.3664.
31. Kannappan V, Ali M, Small B, Rajendran G, Elzawawy A, Thakur M, et al. Advances in repurposing disulfiram as copper‑dependent anticancer agent. Front Mol Biosci. 2021;8:741316. https://doi.org/10.3389/fmolb.2021.741316.
32. Werlenius K, Kinhult S, Solheim TS, Bernhardt P, Carén H, Jakola AS, et al. Disulfiram + copper vs chemotherapy alone in recurrent glioblastoma. JAMA Netw Open. 2023;6:e234149. https://doi.org/10.1001/jamanetworkopen.2023.4149.
33. Madala HR, Punganuru SR, Ali Osman F, Zhang H, Durrant D, Kallifatidis G, et al. Brain‑penetrating disulfiram nanoparticles: cytotoxicity and efficacy. Oncotarget. 2017;9:3459‑82. https://doi.org/10.18632/oncotarget.23320.
34. Tsuda H, Koga M, Nojima M, Kikuchi Y, Koyama T, Saito S, et al. Survival changes in HIV: surveys from Tokyo. J Infect Chemother. 2021;27:949‑56. https://doi.org/10.1016/j.jiac.2021.02.003.
35. Matsuda K, Maeda K. HIV reservoirs and strategies for cure. Int J Mol Sci. 2024;25:2621. https://doi.org/10.3390/ijms25052621.
36. Xing S, Bullen CK, Shroff NS, Shan L, Yang HC, Manucci JL, et al. Disulfiram reactivates latent HIV‑1 without global T‑cell activation. J Virol. 2011;85:6060‑4. https://doi.org/10.1128/JVI.02033‑10.
37. Duggan NN, Dragic T, Chanda SK, Patel M, Li W, Goff SP, et al. Regulation of HIV latency on path to cure. Viruses. 2023;15:2435. https://doi.org/10.3390/v15122435.
38. Doyon G, Zerbato J, Mellors JW, Sluis‑Cremer N, Sluis‑Cremer N, Bosque A, et al. Disulfiram reactivates HIV‑1 via PTEN depletion. AIDS. 2013;27:F7‑11. https://doi.org/10.1097/QAD. 0b013e3283570620.
39. Spivak AM, Andrade A, Eisele E, Hoh R, Bacchetti P, Buckheit RW, et al. Pilot study of disulfiram as latency‑reversing agent. Clin Infect Dis. 2014;58:883‑90. https://doi.org/10.1093/cid/cit813.
40. Elliott JH, McMahon JH, Chang CC, Lee SA, Hartogensis W, Pilcher CD, et al. Disulfiram to reverse HIV latency: phase 2 trial. Lancet HIV. 2015;2:e520‑9. https://doi.org/10.1016/S2352‑3018(15)00226‑X.
41. McMahon JH, Evans VA, Lau JSY, Chang CC, Deeks SG, Lewin SR, et al. Neurotoxicity with high‑dose disulfiram + vorinostat. AIDS. 2022;36:75‑82. https://doi.org/10.1097/QAD.0000000000003091.
42. Wei DG, Chiang V, Fyne E, Balakrishnan M, Barnes T, Graettinger J, et al. Romidepsin induces HIV expression ex vivo. PLoS Pathog. 2014;10:e1004071. https://doi.org/10.1371/journal.ppat.1004071.
43. Kula A, Delacourt N, Bouchat S, Darcis G, Avettand‑Fenoel V, Mélard A, et al. Heterogeneous HIV‑1 reactivation by disulfiram ± romidepsin. J Acquir Immune Defic Syndr. 2019;80:605‑13. https://doi.org/10.1097/QAI.0000000000001958.
44. Tamburin S, Mantovani E, De Bernardis E, Leonardi M, Buja A, Cernetti R, et al. COVID‑19 symptoms in patients taking disulfiram. Intern Emerg Med. 2021;16:1729‑31. https://doi.org/10.1007/s11739‑021‑02633‑y.
45. Chen HF, Hsueh PR, Liu YY, Chang CJ, Huang YC, Hsu CW, et al. Disulfiram blocks SARS‑CoV‑2 entry via Spike‑ACE2 inhibition. Am J Cancer Res. 2022;12:3333‑46. PMID:35968340.
46. Monticolo F, Palomba E, Termolino P, Colombo F, Giarola V, Montagnese C, et al. Extracellular DNA and NETs/RETs/biofilms. Front Plant Sci. 2020;11:589837. https://doi.org/10.3389/fpls.2020.589837.
47. Leppkes M, Schick M, Hohberger B, Mahajan A, Eelen G, Knopf J, et al. Updates on NET formation. Semin Arthritis Rheum. 2019;49(3S):S43‑8. https://doi.org/10.1016/j.semarthrit.2019.09.011.
48. Adrover JM, Carrau L, Daßler‑Plenker J, Rasper D, Liszewski M, Shilatifard A, et al. Disulfiram inhibits NETs and protects against SARS‑CoV‑2. JCI Insight. 2022;7:e157342. https://doi.org/10.1172/jci.insight.157342.
49. Fillmore N, Bell S, Shen C, Nguyen V, La J, Kang M, et al. Disulfiram use is associated with lower risk of COVID‑19. PLoS One. 2021;16:e0259061. https://doi.org/10.1371/journal.pone.0259061.
50. ClinicalTrials.gov. Study NCT04485130: DISCO trial. Available from: https://clinicaltrials.gov/ct2/show/NCT04485130. Accessed 2025 May 16.
51. ClinicalTrials.gov. Study NCT04594343: Disulfiram in moderate COVID‑19. Available from: https://clinicaltrials.gov/ct2/show/NCT04594343. Accessed 2025 May 16.
52. Takeo S. Repurposing disulfiram as a treatment option for chronic Lyme disease. Int J Neuropsychopharmacol. 2025;28:i236‑7. https://doi.org/10.1093/ijnp/pyae059.414.
53. Liegner KB. Disulfiram in treatment of Lyme disease: 3 case report. Antibiotics. 2019;8:72. https://doi.org/10.3390/antibiotics8020072.
54. Lee YM, Duh Y, Wang ST, Lai MM, Yuan HS, Lim C. Targeting Zn site in HCV NS5A with disulfiram. J Am Chem Soc. 2016;138:3856‑62. https://doi.org/10.1021/jacs.6b00299.
55. Sheppard JG, Frazier KR, Saralkar P, Hossain MD, Ramos K, White KL, et al. Disulfiram‑based disulfides as antibacterial agents. Bioorg Med Chem Lett. 2018;28:1298‑302. https://doi.org/10.1016/j.bmcl.2018.03.023.
56. Long TE. Repurposing thiram and disulfiram as antibacterial agents. Antimicrob Agents Chemother. 2017;61:e00898‑17. https://doi.org/10.1128/AAC.00898‑17.
57. Serafin MB, Foletto VS, da Rosa TF, Machado CS, Vahl CF, Silva Junior A, et al. Disulfiram + vancomycin against MDR Enterococcus. Curr Microbiol. 2022;79:137. https://doi.org/10.1007/s00284‑022‑02794‑9.
58. Shirley DA, Sharma I, Warren CA, Moonah S. Disulfiram as antiparasitic. Front Cell Infect Microbiol. 2021;11:633194. https://doi.org/10.3389/fcimb.2021.633194.
59. Peniche AG, Renslo AR, Melby PC, Travi BL. Thiuram disulfides with metal ions in Leishmania. Antimicrob Agents Chemother. 2015; 59:6463‑70. https://doi.org/10.1128/AAC.05131‑14.
60. Lajarin Reinares M, Martinez Esteve E, Pena Rodríguez E, Gómez ML, Roca E, Díaz C, et al. Fixed‑dose combination disulfiram + benzyl benzoate. Int J Mol Sci. 2022;23:10969. https://doi.org/10.3390/ijms231810969.
61. Castillo Villanueva A, Rufino González Y, Méndez ST, García R, Romero M, Sánchez G, et al. Disulfiram inhibits Giardia TIM. Int J Parasitol Drugs Drug Resist. 2017;7:425‑32. https://doi.org/10.1016/j.ijpddr.2017.11.003.
62. Traccis F, Minozzi S, Trogu E, Contu P, Casu G, Porcu M, et al. Disulfiram for cocaine dependence. Cochrane Database Syst Rev. 2024;1:CD007024. https://doi.org/10.1002/14651858.CD007024.pub3.
63. Butcher K, Kannappan V, Kilari RS, Pandey MK, Selvam C, Babu A, et al. Chemical structures related to anticancer activity of disulfiram. BMC Cancer. 2018;18:753. https://doi.org/10.1186/s12885‑018‑4617‑x.
64. Gao X, Huang H, Pan C, Yang Z, Wang C, Liu Y, et al. Disulfiram/copper enhances CD47 blockade in hepatocellular carcinoma. Cancers (Basel). 2022;14:4715. https://doi.org/10.3390/cancers 14194715.
65. Wehbe M, Anantha M, Shi M, Leung A, Bally MB, Brodt P, et al. Copper diethyldithiocarbamate injectable formulation. Int J Nanomedicine. 2017;12:4129‑46. https://doi.org/10.2147/IJN.S137347.
66. Heroux D, Leung AWY, Gilabert‑Oriol R, Tran TH, D’Souza S, Gauthier MA, et al. Liposomal disulfiram metabolite enhances copper‑mediated tumor immunity. Int J Pharm. 2025;683:126010. https://doi.org/10.1016/j.ijpharm.2025.126010.
67. Ho WJ, Jaffee EM, Zheng L. Tumor microenvironment in pancreatic cancer. Nat Rev Clin Oncol. 2020;17:527‑40. https://doi.org/10.1038/s41571‑020‑0363‑5.
68. Manini I, Caponnetto F, Bartolini A, Ius T, Skrap M, Beltrami AP, et al. Role of microenvironment in glioma invasion. Int J Mol Sci. 2018;19:147. https://doi.org/10.3390/ijms19010147.
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Alicja Pszczółkowska, Zofia Piniewska, Kalina Kujawska, Weronika Wiśniewska, Maria Mikołajczuk, Dominika Bulczyńska, Katarzyna Dettlaff (Autor)
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
