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Systematic Review

Clinical, pharmacological, and formulation evaluation of disulfiram in the treatment of glioblastoma - a systematic literature review

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Pages 541-557 | Received 18 Oct 2022, Accepted 09 Mar 2023, Published online: 21 Mar 2023

References

  • Miller KD, Ostrom QT, Kruchko C, et al. Brain and other central nervous system tumor statistics, 2021. CA Cancer J Clin. 2021;71(5):381–406. DOI:10.3322/caac.21693
  • Cote DJ, Ostrom QT. Epidemiology and etiology of glioblastoma. In: Otero J Becker A, editors. Precision molecular pathology of glioblastoma. Cham: Springer International Publishing; 2021. p. 3–19.
  • Cha GD, Kang T, Baik S, et al. Advances in drug delivery technology for the treatment of glioblastoma multiforme. J Control Release. 2020;328:350–367.
  • Alifieris C, Trafalis DT. Glioblastoma multiforme: pathogenesis and treatment. Pharmacol Ther. 2015;152:63–82.
  • Grochans S, Cybulska AM, Simińska D, et al. Epidemiology of glioblastoma multiforme-literature review. Cancers (Basel). 2022;14(10):2412. DOI:10.3390/cancers14102412
  • Rajaratnam V, Islam MM, Yang M, et al. Glioblastoma: pathogenesis and current status of chemotherapy and other novel treatments. Cancers (Basel). 2020;12(4):937. DOI:10.3390/cancers12040937
  • Louis DN, Perry A, Wesseling P, et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol. 2021;23(8):1231–1251. DOI:10.1093/neuonc/noab106
  • Hanif F, Muzaffar K, Perveen K, et al. Glioblastoma multiforme: a review of its epidemiology and pathogenesis through clinical presentation and treatment. Asian Pac J Cancer Prev. 2017;18(1):3–9. DOI:10.22034/APJCP.2017.18.1.3
  • Rønning PA, Helseth E, Meling TR, et al. A population-based study on the effect of temozolomide in the treatment of glioblastoma multiforme. Neuro Oncol. 2012;14(9):1178–1184. DOI:10.1093/neuonc/nos153
  • Halatsch ME, Kast RE, Karpel-Massler G, et al. A phase Ib/IIa trial of 9 repurposed drugs combined with temozolomide for the treatment of recurrent glioblastoma: cUSP9v3. Neurooncol Adv. 2021;3(1):vdab075. DOI:10.1093/noajnl/vdab075. .
  • Shergalis A, Bankhead A, Luesakul U, et al. Current challenges and opportunities in treating glioblastoma. Pharmacol Rev. 2018;70(3):412–445. DOI:10.1124/pr.117.014944
  • Huang JY, Campian JL, Gujar AD, et al. A phase I study to repurpose disulfiram in combination with temozolomide to treat newly diagnosed glioblastoma after chemoradiotherapy. J Neurooncol. 2016;128(2):259–266. DOI:10.1007/s11060-016-2104-2
  • Stokes M, Abdijadid S. Disulfiram. Treasure Island: StatPearls Publishing; 2021.
  • Lu Y, Pan Q, Gao W, et al. Leveraging disulfiram to treat cancer: mechanisms of action, delivery strategies, and treatment regimens. Biomaterials. 2022;281:121335.
  • Eneanya DI, Bianchine JR, Duran DO, et al. The actions of metabolic fate of disulfiram. Annu Rev Pharmacol Toxicol. 1981;21:575–596.
  • Sauna ZE, Shukla S, Ambudkar SV. Disulfiram, an old drug with new potential therapeutic uses for human cancers and fungal infections. Mol Biosyst. 2005;1(2):127–134.
  • Shirley DA, Sharma I, Warren CA, et al. Drug repurposing of the alcohol abuse medication disulfiram as an anti-parasitic agent. Front Cell Infect Microbiol. 2021;11:633194.
  • Farooq MA, Aquib M, Khan DH, et al. Recent advances in the delivery of disulfiram: a critical analysis of promising approaches to improve its pharmacokinetic profile and anticancer efficacy. Daru. 2019;27(2):853–862. DOI:10.1007/s40199-019-00308-w
  • De Sousa A. Disulfiram: its use in alcohol dependence and other disorders. Singapore: Springer Singapore; 2020.
  • Omran Z, Sheikh R, Baothman OA, et al. Repurposing disulfiram as an anti-obesity drug: treating and preventing obesity in high-fat-fed rats. Diabetes Metab Syndr Obes. 2020;13:1473–1480.
  • Nagai N, Yoshioka C, Mano Y, et al. A nanoparticle formulation of disulfiram prolongs corneal residence time of the drug and reduces intraocular pressure. Exp Eye Res. 2015;132:115–123.
  • Lin M-H, Moses DC, Hsieh C-H, et al. Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via different modes. Antiviral Res. 2018;150:155–163.
  • Frazier KR, Moore JA, Long TE. Antibacterial activity of disulfiram and its metabolites. J Appl Microbiol. 2019;126(1):79–86.
  • Meneguello JE, Murase LS, de Souza JVP, et al. Systematic review of disulfiram as an antibacterial agent: what is the evidence? Int J Antimicrob Agents. 2022;59(5):106578. DOI:10.1016/j.ijantimicag.2022.106578
  • Shanholtzer CN, Rice C, Watson K, et al. Effect of copper on the antifungal activity of disulfiram (Antabuse®) in fluconazole-resistant Candida strains. Med Mycol. 2022;60(4):myac016. DOI:10.1093/mmy/myac016
  • Hao W, Qiao D, Han Y, et al. Identification of disulfiram as a potential antifungal drug by screening small molecular libraries. J Infect Chemother. 2021;27(5):696–701. DOI:10.1016/j.jiac.2020.12.012
  • Chen H-F, Hsueh P-R, Liu Y-Y, et al. Disulfiram blocked cell entry of SARS-CoV-2 via inhibiting the interaction of spike protein and ACE2. Am J Cancer Res. 2022;12(7):3333–3346.
  • Elliott JH, McMahon JH, Chang CC, et al. Short-term administration of disulfiram for reversal of latent HIV infection: a phase 2 dose-escalation study. Lancet HIV. 2015;2(12):e520–9. DOI:10.1016/S2352-3018(15)00226-X
  • Lee SA, Elliott JH, McMahon J, et al. Population pharmacokinetics and pharmacodynamics of disulfiram on inducing latent HIV-1 transcription in a phase IIb trial. Clin Pharmacol Ther. 2019;105(3):692–702. DOI:10.1002/cpt.1220
  • Lu C, Li XY, Ren YY, et al. Disulfiram: a novel repurposed drug for cancer therapy. Cancer Chemother Pharmacol. 2021;87(2):159–172. DOI:10.1007/s00280-020-04216-8
  • Zirjacks L, Stransky N, Klumpp L, et al. Repurposing disulfiram for targeting of glioblastoma stem cells: an in vitro study. Biomolecules. 2021;11(11):1561. DOI:10.3390/biom11111561. .
  • Kast RE, Belda-Iniesta C. Suppressing glioblastoma stem cell function by aldehyde dehydrogenase inhibition with chloramphenicol or disulfiram as a new treatment adjunct: a hypothesis. Curr Stem Cell Res Ther. 2009;4(4):314–317.
  • Hothi P, Martins TJ, Chen LP, et al. High-throughput chemical screens identify disulfiram as an inhibitor of human glioblastoma stem cells. Oncotarget. 2012;3(10):1124–1136. DOI:10.18632/oncotarget.707
  • Brown S, Wang WG, Darling JL. Combination treatment of glioblastoma multiforme (GBM) in vitro with disulfiram and copper increases sensitivity to cytotoxic drugs by blocking NF8 B activity and increasing levels of intracellular reactive oxygen species (ROS). Joint Meeting of the Society for Neuro-Oncology/American Association of Neurological Surgeons/Congress of Neurological Surgeons. 2009 Oct 22-24, New Orleans, LA.
  • Zhao P, Tang X, Huang Y. Teaching new tricks to old dogs: a review of drug repositioning of disulfiram for cancer nanomedicine. VIEW. 2021;24:2020012710.1002/VIW.20200127
  • Cohen JD, Robins HI. Cytotoxicity of diethyldithiocarbamate in human versus rodent cell lines. Invest New Drugs. 1990;8(2):137–142.
  • Rappa F, Cappello F, Halatsch ME, et al. Aldehyde dehydrogenase and HSP90 co-localize in human glioblastoma biopsy cells. Biochimie. 2013;95(4):782–786. DOI:10.1016/j.biochi.2012.11.007
  • Zou H, Li C, Wanggou S, et al. Survival risk prediction models of gliomas based on IDH and 1p/19q. J Cancer. 2020;11(15):4297–4307. DOI:10.7150/jca.43805
  • Laba AE, Ziólkowski P. Trends in glioblastoma treatment research: an analysis of clinical trials and literature. Neurol Neurochir Pol. 2021;55(3):269–280.
  • Kannappan V, Ali M, Small B, et al. Recent advances in repurposing disulfiram and disulfiram derivatives as copper-dependent anticancer agents. Front Mol Biosci. 2021;8:741316.
  • Li H, Wang J, Wu C, et al. The combination of disulfiram and copper for cancer treatment. Drug Discov Today. 2020;25(6):1099–1108. DOI:10.1016/j.drudis.2020.04.003
  • Viola-Rhenals M, Patel KR, Jaimes-Santamaria L, et al. Recent advances in Antabuse (disulfiram): the importance of its metal-binding ability to its anticancer activity. Curr Med Chem. 2018;25(4):506–524. DOI:10.2174/0929867324666171023161121
  • Wang W, Darling JL. How could a drug used to treat alcoholism also be effective against glioblastoma? Expert Rev Anticancer Ther. 2013;13(3):239–241.
  • Zhong S, Shengyu L, Xin S, et al. Disulfiram in glioma: literature review of drug repurposing. Front Pharmacol. 2022;13:933655.
  • Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1–34. DOI:10.1016/j.jclinepi.2009.06.006
  • Karamanakos PN, Trafalis DT, Papachristou DJ, et al. Evidence for the efficacy of disulfiram and copper combination in glioblastoma multiforme - a propos of a case. J Buon. 2018;22(5):1227–1232.
  • Orcheston-Findlay L, Bax S, Utama R, et al. Advanced spheroid, tumouroid and 3D bioprinted in-vitro models of adult and paediatric glioblastoma. Int J Mol Sci. 2021;22(6):2962. DOI:10.3390/ijms22062962
  • Kapałczyńska M, Kolenda T, Przybyła W, et al. 2D and 3D cell cultures - a comparison of different types of cancer cell cultures. Arch Med Sci. 2018;14(4):910–919. DOI:10.5114/aoms.2016.63743
  • da Hora Cc, Schweiger MW, Wurdinger T, et al. Patient-derived glioma models: from patients to dish to animals. Cells. 2019;8(10):1177. DOI:10.3390/cells8101177
  • Neufeld L, Yeini E, Reisman N, et al. Microengineered perfusable 3D-bioprinted glioblastoma model for in vivo mimicry of tumor microenvironment. Sci Adv. 2021;7(34):eabi9119. DOI:10.1126/sciadv.abi9119
  • Tang M, Tiwari SK, Agrawal K, et al. Rapid 3D bioprinting of glioblastoma model mimicking native biophysical heterogeneity. Small. 2021;17(15):2006050. DOI:10.1002/smll.202006050
  • Huang JY, Campian JL, Gujar AD, et al. Final results of a phase I dose-escalation, dose-expansion study of adding disulfiram with or without copper to adjuvant temozolomide for newly diagnosed glioblastoma. J Neurooncol. 2018;138(1):105–111. DOI:10.1007/s11060-018-2775-y
  • Huang JY, Chaudhary R, Cohen AL, et al. A multicenter phase II study of temozolomide plus disulfiram and copper for recurrent temozolomide-resistant glioblastoma. J Neurooncol. 2019;142(3):537–544. DOI:10.1007/s11060-019-03125-y. .
  • Halatsch ME, Dwucet A, Schmidt CJ, et al. In vitro and clinical compassionate use experiences with the drug-repurposing approach CUSP9v3 in glioblastoma. Pharmaceuticals. 2021;14(12):1241. DOI:10.3390/ph14121241
  • Lun XQ, Wells JC, Grinshtein N, et al. Disulfiram when combined with copper enhances the therapeutic effects of temozolomide for the treatment of glioblastoma. Clin Cancer Res. 2016;22(15):3860–3875. DOI:10.1158/1078-0432.CCR-15-1798
  • Koh HK, Seo SY, Kim JH, et al. Disulfiram, a re-positioned aldehyde dehydrogenase inhibitor, enhances radiosensitivity of human glioblastoma cells in vitro. Cancer Res Treat. 2019;51(2):696–705. DOI:10.4143/crt.2018.249
  • Kannappan V, Liu Y, Wang Z, et al. PLGA-nano-encapsulated disulfiram inhibits hypoxia-induced NFκB, cancer stem cells and targets glioblastoma in vitro and in vivo. Mol Cancer Ther. 2022;21:1273–1284.
  • Mettang M, Meyer-Pannwitt V, Karpel-Massler G, et al. Blocking distinct interactions between glioblastoma cells and their tissue microenvironment: a novel multi-targeted therapeutic approach. Sci Rep. 2018;8:14.
  • Zhao PF, Wang YH, Kang XJ, et al. Dual-targeting biomimetic delivery for anti-glioma activity via remodeling the tumor microenvironment and directing macrophagemediated immunotherapy. Chem Sci. 2018;9(10):2674–2689. DOI:10.1039/C7SC04853J
  • Zheng ZN, Zhang JX, Jiang JZ, et al. Remodeling tumor immune microenvironment (TIME) for glioma therapy using multi-targeting liposomal codelivery. J Immunother Cancer. 2020;8(2):16. DOI:10.1136/jitc-2019-000207
  • Liu CC, Wu CL, Lin MX, et al. Disulfiram sensitizes a therapeutic-resistant glioblastoma to the TGF-β receptor inhibitor. Int J Mol Sci. 2021;22(19):10496. DOI:10.3390/ijms221910496
  • Halatsch ME, Kast RE, Dwucet A, et al. Bcl-2/bcl-xL inhibition predominantly synergistically enhances the anti-neoplastic activity of a low-dose CUSP9 repurposed drug regime against glioblastoma. Br J Pharmacol. 2019;176(18):3681–3694. DOI:10.1111/bph.14773
  • Rezaei N, Neshasteh-Riz A, Mazaheri Z, et al. The combination of metformin and disulfiram-Cu for effective radiosensitization on glioblastoma cells. Cell J. 2020;22(3):263–272. DOI:10.22074/cellj.2020.6798
  • Liu P, Brown S, Goktug T, et al. Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells. Br J Cancer. 2012;107(9):1488–1497. DOI:10.1038/bjc.2012.442
  • Garrett AM, Lastakchi S, McConville C. The personalisation of glioblastoma treatment using whole exome sequencing: a pilot study. Genes (Basel). 2020;11(2):173.
  • Lastakchi S, Olaloko MK, McConville C. A potential new treatment for high-grade glioma: a study assessing repurposed drug combinations against patient-derived high-grade glioma cells. Cancers (Basel). 2022;14(11):21.
  • Strømme JH, Eldjarn L. Distribution and chemical forms of diethyldithiocarbamate and tetraethylthiuram disulphide (disulfiram) in mice in relation to radioprotection. Biochem Pharmacol. 1966;15(3):287–297.
  • Jia Y, Huang T. Overview of Antabuse(®) (disulfiram) in radiation and cancer biology. Cancer Manag Res. 2021;13:4095–4101.
  • Babak MV, Ahn D. Modulation of intracellular copper levels as the mechanism of action of anticancer copper complexes: clinical relevance. Biomedicines. 2021;9(8):852.
  • Paranjpe A, Zhang RW, Ali-Osman F, et al. Disulfiram is a direct and potent inhibitor of human O-6-methylguanine-DNA methyltransferase (MGMT) in brain tumor cells and mouse brain and markedly increases the alkylating DNA damage. Carcinogenesis. 2014;35(3):692–702. DOI:10.1093/carcin/bgt366
  • Li Y, Fu SY, Wang LH, et al. Copper improves the anti-angiogenic activity of disulfiram through the EGFR/Src/VEGF pathway in gliomas. Cancer Lett. 2015;369(1):86–96. DOI:10.1016/j.canlet.2015.07.029
  • Qu Y, Sun X, Ma L, et al. Therapeutic effect of disulfiram inclusion complex embedded in hydroxypropyl-beta-cyclodextrin on intracranial glioma-bearing male rats via intranasal route. Eur J Pharm Sci. 2021;156:7.
  • Qu Y, Li A, Ma L, et al. Nose-to-brain delivery of disulfiram nanoemulsion in situ gel formulation for glioblastoma targeting therapy. Int J Pharm. 2021;597:10.
  • Lewis DJ, Deshmukh P, Tedstone AA, et al. On the interaction of copper(ii) with disulfiram. Chem Commun. 2014;50(87):13334–13337. DOI:10.1039/C4CC04767B
  • Skaga E, Skaga IØ, Grieg Z, et al. The efficacy of a coordinated pharmacological blockade in glioblastoma stem cells with nine repurposed drugs using the CUSP9 strategy. J Cancer Res Clin Oncol. 2019;145(6):1495–1507. DOI:10.1007/s00432-019-02920-4
  • Kast RE, Alfieri A, Assi HI, et al. MDACT: a new principle of adjunctive cancer treatment using combinations of multiple repurposed drugs, with an example regimen. Cancers (Basel). 2022;14(10):2563. DOI:10.3390/cancers14102563
  • Gessner PK, Gessner T. Disulfiram and its metabolite, diethyldithiocarbamate: pharmacology and status in the treatment of alcoholism, HIV infections, AIDS and heavy metal toxicity. In: Chapter 1, Introduction and scope of monograph. Dordrecht: Springer Netherlands, 1992: p. 1–6. DOI:10.1007/978-94-011-2328-0_1.
  • Gessner PK, Gessner T. Disulfiram and its metabolite, diethyldithiocarbamate: pharmacology and status in the treatment of alcoholism, HIV infections, AIDS and heavy metal toxicity. In: Chapter 5, Metabolism of disulfiram and diethyldithiocarbamate. Dordrecht: Springer Netherlands, 1992: p. 29–42 doi:10.1007/978-94-011-2328-0_5.
  • Qiu C, Zhang X, Huang B, et al. Disulfiram, a ferroptosis inducer, triggers lysosomal membrane permeabilization by up-regulating ROS in glioblastoma. Onco Targets Ther. 2020;13:10631–10640.
  • McConville C, Tawari P, Wang WG. Hot melt extruded and injection moulded disulfiram-loaded PLGA millirods for the treatment of glioblastoma multiforme via stereotactic injection. Int J Pharm. 2015;494(1):73–82.
  • Westhoff MA, Zhou SX, Nonnenmacher L, et al. Inhibition of NF-kappa B signaling ablates the invasive phenotype of glioblastoma. Mol Cancer Res. 2013;11(12):1611–1623. DOI:10.1158/1541-7786.MCR-13-0435-T
  • Skrott Z, Mistrik M, Andersen KK, et al. Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature. 2017;552(7684):194–199. DOI:10.1038/nature25016
  • Lenin S, Ponthier E, Scheer KG, et al. A drug screening pipeline using 2D and 3D patient-derived in vitro models for pre-clinical analysis of therapy response in glioblastoma. Int J Mol Sci. 2021;22(9):4322. DOI:10.3390/ijms22094322
  • Triscott J, Lee C, Hu KJ, et al. Disulfiram, a drug widely used to control alcoholism, suppresses self-renewal of glioblastoma and overrides resistance to temozolomide. Oncotarget. 2012 Oct;3(10):1112–1123.
  • Johansson B. A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites. Acta Psychiatr Scand. 1992;86(Suppl 369):15–26.
  • Petersen EN. The pharmacology and toxicology of disulfiram and its metabolites. Acta Psychiatr Scand. 1992;86(Suppl 369):7–13.
  • Gessner PK, Gessner T. Disulfiram and its metabolite, diethyldithiocarbamate: pharmacology and status in the treatment of alcoholism, HIV infections, AIDS and heavy metal toxicity. In Disulfiram and diethyldithiocarbamate as enzyme inhibitors. Dordrecht: Springer Netherlands; 1992; p. 95–135. Chapter 8.
  • Koppaka V, Thompson DC, Chen Y, et al. Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application. Pharmacol Rev. 2012;64(3):520. DOI:10.1124/pr.111.005538
  • Lam JP, Mays DC, Lipsky JJ. Inhibition of recombinant human mitochondrial and cytosolic aldehyde dehydrogenases by two candidates for the active metabolites of disulfiram. Biochemistry. 1997;36(44):13748–13754.
  • Lee YE, Choi SA, Kwack PA, et al. Repositioning disulfiram as a radiosensitizer against atypical teratoid/rhabdoid tumor. Neuro Oncol. 2017;19(8):1079–1087. DOI:10.1093/neuonc/now300
  • Meier S, Cantilena S, Chirou MVN, et al. Alcohol-abuse drug disulfiram targets pediatric glioma via MLL degradation. Cell Death Dis. 2021;12(8):12. DOI:10.1038/s41419-021-04078-9
  • Faiman MD, Artman L, Haya K. Disulfiram distribution and elimination in the rat after oral and intraperitoneal administration. Alcohol Clin Exp Res. 1980;4(4):412–419.
  • Gunasekaran S, Weinstein P, Anderson G, et al. Distribution of disulfiram in brain after carotid ligation in gerbils. Neuropharmacology. 1983;22(9):1159–1163. DOI:10.1016/0028-3908(83)90055-2
  • Ramadhani N, Shabir M, McConville C. Preparation and characterisation of Kolliphor® P 188 and P 237 solid dispersion oral tablets containing the poorly water soluble drug disulfiram. Int J Pharm. 2014;475(1–2):514–522.
  • Chen X, Zhang L, Hu X, et al. Formulation and preparation of a stable intravenous disulfiram‐loaded lipid emulsion. Eur J Lipid Sci Technol. 2015;117(6):869–878. DOI:10.1002/ejlt.201400278
  • Zembko I, Ahmed I, Farooq A, et al. Development of disulfiram-loaded poly(lactic-co-glycolic acid) wafers for the localised treatment of glioblastoma multiforme: a comparison of manufacturing techniques. J Pharm Sci. 2015;104(3):1076–1086. DOI:10.1002/jps.24304
  • Keller L-A, Merkel O, Popp A. Intranasal drug delivery: opportunities and toxicologic challenges during drug development. Drug Deliv Transl Res. 2021;12:735–757.
  • Lan QH, Du CC, Yu RJ, et al. Disulfiram-loaded copper sulfide nanoparticles for potential anti-glioma therapy. Int J Pharm. 2021;607:14.
  • Wehbe M, Malhotra AK, Anantha M, et al. Development of a copper-clioquinol formulation suitable for intravenous use. Drug Deliv Transl Res. 2018;8(1):239–251. DOI:10.1007/s13346-017-0455-7

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