Alcohol-abuse drug disulfiram targets pediatric glioma via MLL degradation
Open accessAbstract
Pediatric gliomas comprise a broad range of brain tumors derived from glial cells. While high-grade gliomas are often resistant to therapy and associated with a poor outcome, children with low-grade gliomas face a better prognosis. However, the treatment of low-grade gliomas is often associated with severe long-term adverse effects. This shows that there is a strong need for improved treatment approaches. Here, we highlight the potential for repurposing disulfiram to treat pediatric gliomas. Disulfiram is a drug used to support the treatment of chronic alcoholism and was found to be effective against diverse cancer types in preclinical studies. Our results show that disulfiram efficiently kills pediatric glioma cell lines as well as patient-derived glioma stem cells. We propose a novel mechanism of action to explain disulfiram’s anti-oncogenic activities by providing evidence that disulfiram induces the degradation of the oncoprotein MLL. Our results further reveal that disulfiram treatment and MLL downregulation induce similar responses at the level of histone modifications and gene expression, further strengthening that MLL is a key target of the drug and explaining its anti-oncogenic properties.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
DIS exerts anti-oncogenic effects by triggering the degradation of the oncoprotein MLL.
“In addition to the aforementioned targets, DIS exerts anti-oncogenic effects by triggering the degradation of the oncoprotein MLL, e.g., MLL1 drives tumor growth and angiogenesis across multiple cancer types; its knockdown potently suppresses in vivo tumor progression.87”
From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [87]
The Results section ('Disulfiram induces MLL degradation'; page unavailable) reports disulfiram-induced MLL1 degradation. The Discussion proposes that MLL degradation contributes to disulfiram’s anti-oncogenic effects, but the claim presents that proposed mechanism as established causation. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Shrestha, S., & Offer, S. M. (2016) · Medical Epigenetics · doi:10.1159/000444713 · Cited by 8,949 · see citing works
High-Resolution Profiling of Histone Methylations in the Human Genome
Barski, A., Cuddapah, S., Cui, K., Roh, T.-Y., Schones, D. E., Wang, Z., Wei, G., Chepelev, I., & Zhao, K. (2007) · Cell · doi:10.1016/j.cell.2007.05.009 · Cited by 6,845 · see citing works
Can the pharmaceutical industry reduce attrition rates?
Kola, I., & Landis, J. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1470 · Cited by 4,167 · see citing works
A pathology atlas of the human cancer transcriptome
Uhlen, M., Zhang, C., Lee, S., Sjöstedt, E., Fagerberg, L., Bidkhori, G., Benfeitas, R., Arif, M., Liu, Z., Edfors, F., et al. (2017) · Science · doi:10.1126/science.aan2507 · Cited by 3,371 · see citing works
Epigenetic therapy of cancer: past, present and future
Yoo, C. B., & Jones, P. A. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd1930 · Cited by 1,291 · see citing works
Genome Regulation by Polycomb and Trithorax: 70 Years and Counting
Schuettengruber, B., Bourbon, H.-M., Di Croce, L., & Cavalli, G. (2017) · Cell · doi:10.1016/j.cell.2017.08.002 · Cited by 1,094 · see citing works
Eilers, M., & Eisenman, R. N. (2008) · Genes & Development · doi:10.1101/gad.1712408 · Cited by 927 · see citing works
Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4
Skrott, Z., Mistrik, M., Andersen, K. K., Friis, S., Majera, D., Gursky, J., Ozdian, T., Bartkova, J., Turi, Z., Moudry, P., et al. (2017) · Nature · doi:10.1038/nature25016 · Cited by 807 · see citing works
The Genetic Landscape of the Childhood Cancer Medulloblastoma
Parsons, D. W., Li, M., Zhang, X., Jones, S., Leary, R. J., Lin, J., Boca, S. M., Carter, H. K., Samayoa, J. A., Bettegowda, C., et al. (2010) · Science · doi:10.1126/science.1198056 · Cited by 708 · see citing works
Hijacked in cancer: the MLL/KMT2 family of methyltransferases
Rao, R., & Dou, Y. (2015) · Nature Reviews. Cancer · doi:10.1038/nrc3929 · Cited by 558 · see citing works
The Oligodendroglial Lineage Marker OLIG2 Is Universally Expressed in Diffuse Gliomas
Ligon, K., Alberta, J., Kho, A., Weiss, J., Kwaan, M. R., Nutt, C., Louis, D., Stiles, C., & Rowitch, D. (2004) · Journal of Neuropathology and Experimental Neurology · doi:10.1093/jnen/63.5.499 · Cited by 467 · see citing works
Wang, P., Lin, C., Smith, E. R., Guo, H. W., Sanderson, B. W., Wu, M., Gogol, M., Alexander, T. B., Seidel, C. W., Wiedemann, L. M., et al. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00924-09 · Cited by 360 · see citing works
Sleire, L., Førde, H. E., Netland, I. A., Leiss, L., Skeie, B. S., & Enger, P. Ø. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.07.013 · Cited by 329 · see citing works
Liu, P., Brown, S., Goktug, T., Channathodiyil, P., Kannappan, V., Hugnot, J.-P., Guichet, P., Bian, X., Armesilla, A. L., Darling, J. L., et al. (2012) · British Journal of Cancer · doi:10.1038/bjc.2012.442 · Cited by 300 · see citing works
Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development
Glaser, S. P., Schaft, J., Lubitz, S., Vintersten, K., van der Hoeven, F., Tufteland, K. R., Aasland, R., Anastassiadis, K., Ang, S., & Stewart, A. F. (2006) · Development · doi:10.1242/dev.02302 · Cited by 289 · see citing works
Targeting Transcription Factors in Cancer
Bhagwat, A. S., & Vakoc, C. R. (2015) · Trends in Cancer · doi:10.1016/j.trecan.2015.07.001 · Cited by 276 · see citing works
Rheinbay, E., Suvà, M. L., Gillespie, S. M., Wakimoto, H., Patel, A. P., Shahid, M., Oksuz, O., Rabkin, S. D., Martuza, R. L., Rivera, M. N., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.04.021 · Cited by 268 · see citing works
The MLL1-H3K4me3 Axis-Mediated PD-L1 Expression and Pancreatic Cancer Immune Evasion
Lu, C., Paschall, A. V., Shi, H., Savage, N. M., Waller, J. L., Sabbatini, M. E., Oberlies, N. H., Pearce, C. J., & Liu, K. (2016) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djw283 · Cited by 264 · see citing works
The thioredoxin reductase/thioredoxin system: Novel redox targets for cancer therapy
Biaglow, J. E., & Miller, R. A. (2005) · Cancer Biology & Therapy · doi:10.4161/cbt.4.1.1434 · Cited by 245 · see citing works
ZF-CxxC domain-containing proteins, CpG islands and the chromatin connection
Long, H. K., Blackledge, N. P., & Klose, R. J. (2013) · Biochemical Society Transactions · doi:10.1042/bst20130028 · Cited by 243 · see citing works
Pax genes: regulators of lineage specification and progenitor cell maintenance
Blake, J. A., & Ziman, M. R. (2014) · Development · doi:10.1242/dev.091785 · Cited by 214 · see citing works
Lun, X., Wells, J. C., Grinshtein, N., King, J. C., Hao, X., Dang, N.-H., Wang, X., Aman, A., Uehling, D., Datti, A., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1798 · Cited by 197 · see citing works
Gaspar, N., Marshall, L. V., Perryman, L., Bax, D. A., Little, S. E., Viana‐Pereira, M., Sharp, S. Y., Vassal, G., Pearson, A. D. J., Reis, R. M., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-1250 · Cited by 163 · see citing works
Self-citationSOX2 expression and amplification in gliomas and glioma cell lines.
Annovazzi, L., Mellai, M., Caldera, V., Valente, G., & Schiffer, D. (2011) · PubMed · Cited by 162 · see citing works
Costa, B. M., Smith, J. S., Chen, Y., Chen, J., PHILLIPS, H. S., Aldape, K., Zardo, G., Nigro, J. M., James, C. D., Fridlyand, J., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-2189 · Cited by 159 · see citing works
Hothi, P., Martins, T. J., Chen, L., Deleyrolle, L. P., Yoon, J., Reynolds, B. A., & Foltz, G. (2012) · Oncotarget · doi:10.18632/oncotarget.707 · Cited by 158 · see citing works
Histone-Methyltransferase MLL2 (KMT2B) Is Required for Memory Formation in Mice
Kerimoglu, C., Agís‐Balboa, R. C., Kranz, A., Stilling, R. M., Bahari‐Javan, S., Benito, E., Halder, R., Burkhardt, S., Stewart, A. F., & Fischer, A. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.3356-12.2013 · Cited by 155 · see citing works
Hypoxia-induced mixed-lineage leukemia 1 regulates glioma stem cell tumorigenic potential
Heddleston, J. M., Wu, Q., Rivera, M., Minhas, S., Lathia, J. D., Sloan, A. E., Iliopoulos, O., Hjelmeland, A. B., & Rich, J. N. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.109 · Cited by 138 · see citing works
Triscott, J., Lee, C., Hu, K., Fotovati, A., Berns, R., Pambid, M. R., Luk, M. T., Kast, R. E., Kong, E., Toyota, E. B., et al. (2012) · Oncotarget · doi:10.18632/oncotarget.604 · Cited by 138 · see citing works
Bax, D. A., Little, S. E., Gaspar, N., Perryman, L., Marshall, L. V., Viana‐Pereira, M., Jones, T. A., Williams, R. D., Grigoriadis, A. E., Vassal, G., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005209 · Cited by 128 · see citing works
Self-citationLu, F., Chen, Y., Zhao, C., Wang, H., He, D., Xu, L., Wang, J., He, X., Deng, Y., Lu, E. E., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.03.027 · Cited by 120 · see citing works
Repurposing Disulfiram as An Anti-Cancer Agent: Updated Review on Literature and Patents
Ekinci, E., Rohondia, S. O., Khan, R., & Dou, Q. P. (2019) · Recent Patents on Anti-Cancer Drug Discovery · doi:10.2174/1574892814666190514104035 · Cited by 119 · see citing works
Cvek, B. (2011) · Drug Discovery Today · doi:10.1016/j.drudis.2011.12.010 · Cited by 115 · see citing works
Duan, R., Han, L., Wang, Q., Wei, J., Chen, L., Zhang, J., Kang, C., & Wang, L. (2015) · Oncotarget · doi:10.18632/oncotarget.4813 · Cited by 105 · see citing works
Functional analysis of HOXD9 in human gliomas and glioma cancer stem cells
Tabuse, M., Ohta, S., Ohashi, Y., Fukaya, R., Misawa, A., Yoshida, K., Kawase, T., Saya, H., Thirant, C., Chneiweiss, H., et al. (2011) · Molecular Cancer · doi:10.1186/1476-4598-10-60 · Cited by 100 · see citing works
A Tumorigenic MLL-Homeobox Network in Human Glioblastoma Stem Cells
Gallo, M., Ho, J. S. L., Coutinho, F. J., Vanner, R. J., Lee, L., Head, R., Ling, E. K. M., Clarke, I. D., & Dirks, P. B. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-1881 · Cited by 93 · see citing works
Ansari, K. I., Kasiri, S., & Mandal, S. S. (2012) · Oncogene · doi:10.1038/onc.2012.352 · Cited by 77 · see citing works
Veverka, K. A., Johnson, K. L., Mays, D. C., Lipsky, J. J., & Naylor, S. (1997) · Biochemical Pharmacology · doi:10.1016/s0006-2952(96)00767-8 · Cited by 73 · see citing works
Papaioannou, M., Mylonas, I. G., Kast, R. E., & Brüning, A. (2013) · Oncoscience · doi:10.18632/oncoscience.5 · Cited by 41 · see citing works
KMT2A promotes melanoma cell growth by targeting hTERT signaling pathway
Zhang, C., Song, C., Liu, T., Tang, R., Chen, M., Gao, F., Xiao, B., Qin, G., Shi, F., Li, W., et al. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.285 · Cited by 35 · see citing works
Regulation of IL-20 Expression by Estradiol through KMT2B-Mediated Epigenetic Modification
Su, C.-H., Lin, I., Tzeng, T., Hsieh, W.-T., & Hsu, M. (2016) · PLoS ONE · doi:10.1371/journal.pone.0166090 · Cited by 26 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [42]Ansari KI Kasiri S Mandal SS Histone methylase MLL1 has critical roles in tumor growth and angiogenesis and its knockdown suppresses tumor growth in vivo Oncogene. 2013 32 3359 70 10.1038/onc.2012.352 22926525 PMC3511651 · DOI
Cited by
Sorted by citations
Recent progress in DNA methyltransferase inhibitors as anticancer agents
Zhang, Z., Wang, G., Li, Y., Lei, D., Xiang, J., Ouyang, L., Wang, Y., & Yang, J. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1072651 · Cited by 149 · see citing works
Glioblastoma: Current Status, Emerging Targets, and Recent Advances
Thakur, A., Faujdar, C., Sharma, R., Sharma, S., Malik, B., Nepali, K., & Liou, J. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01946 · Cited by 120 · see citing works
Werlenius, K., Kinhult, S., Solheim, T. S., Magelssen, H., Löfgren, D., Mudaisi, M., Hylin, S., Bartek, J. J., Strandéus, M., Lindskog, M., et al. (2023) · JAMA Network Open · doi:10.1001/jamanetworkopen.2023.4149 · Cited by 74 · see citing works
Zhao, P., Qu, J., Wu, A., Wang, S., Tang, X., Ou, A., Zhang, J., Xu, Y., Zhao, Q., & Huang, Y. (2022) · Nano Today · doi:10.1016/j.nantod.2022.101448 · Cited by 32 · see citing works
Zhang, Q., Chen, Z., Tang, Q., Wang, Z., Lu, J., You, Y., & Wang, H. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05163-3 · Cited by 32 · see citing works
Disulfiram in glioma: Literature review of drug repurposing
Zhong, S., Liu, S., Shi, X., Zhang, X., Li, K., Liu, G., Li, L., Tao, S., Zheng, B., Sheng, W., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.933655 · Cited by 19 · see citing works
Direct targeted therapy for MLL‐fusion‐driven high‐risk acute leukaemias
Cantilena, S., Gasparoli, L., Pal, D., Heidenreich, O. T., Klusmann, J., Martens, J. H. A., Faille, A., Warren, A. J., Karsa, M., Pandher, R., et al. (2022) · Clinical and Translational Medicine · doi:10.1002/ctm2.933 · Cited by 15 · see citing works
Self-citationCPADS: a web tool for comprehensive pancancer analysis of drug sensitivity
Li, K., Yang, H., Lin, A., Xie, J., Wang, H., Zhou, J., Carr, S. R., Liu, Z., Li, X., Zhang, J., et al. (2024) · Briefings in Bioinformatics · doi:10.1093/bib/bbae237 · Cited by 17 · see citing works
Chromá, K., Škrott, Z., Gurský, J., Bačovský, J., Moudrý, P., Buchtová, T., Mistrík, M., & Bártek, J. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04651-w · Cited by 17 · see citing works
Benkő, B.-M., Lamprou, D. A., Sebestyén, A. R., Zelkó, R., & Sebe, I. (2023) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2023.2190581 · Cited by 11 · see citing works
Combined treatment of disulfiram with PARP inhibitors suppresses ovarian cancer
Tang, B., Wu, M. Y., Zhang, L., Jian, S., Lv, S., Lin, T., Zhu, S., Liu, L., Wang, Y., Yi, Z., et al. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1154073 · Cited by 11 · see citing works
Mi, B., & Li, C. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1558881 · Cited by 3 · see citing works
Tan, P. K., Martins, T. J., Becker, P. S., Wechsler‐Reya, R. J., & Crawford, J. R. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1606575 · Cited by 2 · see citing works
Benkő, B.-M., De Brito Parreirinha, N. S., Sebe, I., & Zelkó, R. (2026) · iScience · doi:10.1016/j.isci.2026.115441 · Cited by 2 · see citing works
Zhan, Y., Wang, Y., Wang, P., Zhu, H., Guo, H., Sun, H., & Liu, M. (2023) · Letters in Drug Design & Discovery · doi:10.2174/1570180820666230203113746 · Cited by 1 · see citing works
BindingDB Entry 50016954: Glioblastoma: Current Status, Emerging Targets, and Recent Advances.
BindingDB (2023) · UC San Diego · doi:10.7270/q2d79gfs
- Authors
- Meier, S., Cantilena, S., Niklison Chirou, M. V., Anderson, J., Hargrave, D., Salomoni, P., de Boer, J., & Michod, D.
- Affiliations
- University College London (GB)
- German Center for Neurodegenerative Diseases (DE)
- Corresponding author
- Michod, David
- ORCID
- Venue
- Cell Death & Disease
- Published
- 2021-08-11
- Volume
- 12
- Issue
- 8
- Pages
- 785-785
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC8358054
- OpenAlex
- W3192219796
- Cited by
- 15
- References
- 41
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 7
- FWCI
- 1.83
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- DZNE Pub (submittedVersion, other-oa)
- Funders
- Brain Tumour Charity (BTC 8/197)
- The Olivia Hodson Cancer Fund, Developmental Biology & Cancer Programme, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH.
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- disulfiram, pediatric glioma, drug repurposing, glioma stem cells, histone modifications, gene expression, low-grade glioma, alcoholism treatment
- MeSH terms
- Alcoholism, Auranofin, Child, Disulfiram, Drug Synergism, Glioma, Histones, Humans, Lysine, Methylation, Histone-Lysine N-Methyltransferase, Protein Processing, Post-Translational, Transcription, Genetic, Down-Regulation, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Cell Proliferation, Myeloid-Lymphoid Leukemia Protein, Drug Repositioning, Proteolysis, Neoplasm Grading
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
