ArticleCarcinogenesis2014
Disulfiram is a direct and potent inhibitor of human O6-methylguanine-DNA methyltransferase (MGMT) in brain tumor cells and mouse brain and markedly increases the alkylating DNA damage.
Article in Carcinogenesis, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers, 1 of them a synthesis that pooled it.
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Who cites it
66 citing papers in PubMed, 1 synthesis or guideline pooled it, 120 citations in OpenAlex.
- Proton Pump Inhibitor Use and Survival in Patients With Newly Diagnosed Glioblastoma.JAMA network open · 2025Pooled it
- Effect of Disulfiram and Copper Plus Chemotherapy vs Chemotherapy Alone on Survival in Patients With Recurrent Glioblastoma: A Randomized Clinical Trial.JAMA network open · 2023Trial
- Cysteine-reactive mitigators of small vessel disease-related NOTCH3 mutants.Scientific reports · 2026Article
- Effects of Disulfiram and Copper in Combination with Temozolomide on Survival, Tumor Size and Autophagy Markers in an F98 Rat Glioma Model.International journal of molecular sciences · 2026Article
- A novel HPβCD-Cu(DDC)Scientific reports · 2025Article
- Redox regulation: mechanisms, biology and therapeutic targets in diseases.Signal transduction and targeted therapy · 2025Review
- Exploiting the role of O6-methylguanine-DNA-methyltransferase (MGMT) in gastrointestinal cancers.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Diethyldithiocarbamate-copper complex ignites the tumor microenvironment through NKG2D-NKG2DL axis.Frontiers in immunology · 2025Article
- Review
- Exploring Disulfiram's Anticancer Potential: PLGA Nano-Carriers for Prolonged Drug Delivery and Potential Improved Therapeutic Efficacy.Nanomaterials (Basel, Switzerland) · 2024Article
- The Versatile Attributes of MGMT: Its Repair Mechanism, Crosstalk with Other DNA Repair Pathways, and Its Role in Cancer.Cancers · 2024Review
- Diethyldithiocarbamate-ferrous oxide nanoparticles inhibit human and mouse glioblastoma stemness: aldehyde dehydrogenase 1A1 suppression and ferroptosis induction.Frontiers in pharmacology · 2024Article
- Transferrin-Conjugated PLGA Nanoparticles for Co-Delivery of Temozolomide and Bortezomib to Glioblastoma Cells.ACS applied nano materials · 2023Article
- Review
- Advancing Cancer Therapy with Copper/Disulfiram Nanomedicines and Drug Delivery Systems.Pharmaceutics · 2023Review
- Exosomal microRNA-222-3p increases UVB sensitivity of lens epithelium cells by suppressing MGMT.International ophthalmology · 2023Article
- DNA Alkylation Damage by Nitrosamines and Relevant DNA Repair Pathways.International journal of molecular sciences · 2023Review
- Drug Repurposing, a Fast-Track Approach to Develop Effective Treatments for Glioblastoma.Cancers · 2022Review
- Article
- The Effect of Disulfiram and Copper on Cellular Viability, ER Stress and ALDH Expression of Human Meningioma Cells.Biomedicines · 2022Article
6 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 4 institutions in 1 country.
Funding
Abstract
The alcohol aversion drug disulfiram (DSF) reacts and conjugates with the protein-bound nucleophilic cysteines and is known to elicit anticancer effects alone or improve the efficacy of many cancer drugs. We investigated the effects of DSF on human O(6)-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein and chemotherapy target that removes the mutagenic O(6)-akyl groups from guanines, and thus confers resistance to alkylating agents in brain tumors. We used DSF, copper-chelated DSF or CuCl2-DSF combination and found that all treatments inhibited the MGMT activity in two brain tumor cell lines in a rapid and dose-dependent manner. The drug treatments resulted in the loss of MGMT protein from tumor cells through the ubiquitin-proteasome pathway. Evidence showed that Cys145, a reactive cysteine, critical for DNA repair was the sole site of DSF modification in the MGMT protein. DSF was a weaker inhibitor of MGMT, compared with the established O(6)-benzylguanine; nevertheless, the 24-36h suppression of MGMT activity in cell cultures vastly increased the alkylation-induced DNA interstrand cross-linking, G2/M cell cycle blockade, cytotoxicity and the levels of apoptotic markers. Normal mice treated with DSF showed significantly attenuated levels of MGMT activity and protein in the liver and brain tissues. In nude mice bearing T98 glioblastoma xenografts, there was a preferential inhibition of tumor MGMT. Our studies demonstrate a strong and direct inhibition of MGMT by DSF and support the repurposing of this brain penetrating drug for glioma therapy. The findings also imply an increased risk for alkylation damage in alcoholic patients taking DSF.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.