Evaluation of the accumulation of disulfiram and its copper complex in A549 cells using mass spectrometry
Abstract
The famous alcohol-aversion drug disulfiram (DSF) is a promising candidate for repurposing in cancer therapy, as indicated by many ongoing and completed clinical trials. Existing researches focus on demonstrating that the anti-cancer activity of DSF is enhanced by copper ions, or solving the problem that DSF is easily decomposed in the body to lose its activity. However, the metabolic kinetics of its ultimate anti-cancer metabolite DDC-Cu (bis-diethyldithiocarbamate-copper) in cells and how it exerts anti-cancer mechanisms remain unclear. In this work, mass spectrometric evaluation of the intracellular and extracellular accumulation of DSF and its copper complex DDC-Cu was performed. Combined with cytotoxicity assay, staining analysis and flow cytometry, we found that DDC-Cu could easily pass through the cell membrane of A549 cells, and accumulate intracellularly for a long time. This process can lead to cellular morphological changes, an increase in ROS content, cell cycle arrest in the G0/G1 phase and apoptosis. Besides, molecular cancer-relevant targets of DDC-Cu in cancer cells were further discussed. This work investigated the cytotoxic mechanism of DDC-Cu, which has important clinical significance for its application in cancer therapy.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
The Cu(DDC)2 complex accumulates intracellularly over prolonged periods, triggers cellular morphological changes, elevates ROS levels, arrests the cell cycle in G0/G1 phase, and ultimately induces apoptosis.
“The complex accumulates intracellularly over prolonged periods. This triggers cellular morphological changes, elevates ROS levels, arrests the cell cycle in G0/G1 phase, and ultimately induces apoptosis.55”
From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [55]
Cites
Jemal, A., Bray, F., Ferlay, J., Ward, E., & Forman, D. (2011) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.20107 · Cited by 54,708 · see citing works
Siegel, R. L., Miller, K. D., & Jemal, A. (2018) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.21442 · Cited by 16,632 · 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
Can you teach old drugs new tricks?
Nosengo, N. (2016) · Nature · doi:10.1038/534314a · Cited by 732 · see citing works
Chen, D., Cui, Q. C., Yang, H., & Dou, Q. P. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-2126 · Cited by 678 · see citing works
Disulfiram treatment of alcoholism. A Veterans Administration cooperative study
Fuller, R. K. (1986) · JAMA · doi:10.1001/jama.256.11.1449 · Cited by 541 · see citing works
Predicting the future burden of cancer
Bray, F., & Møller, B. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1781 · Cited by 489 · see citing works
Disulfiram Treatment of Alcoholism: A Veterans Administration Cooperative Study
Fuller, R. K. (1986) · JAMA · doi:10.1001/jama.1986.03380110055026 · Cited by 431 · see citing works
Deconstructing the Drug Development Process: The New Face of Innovation
Kaitin, K. I. (2010) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2009.293 · Cited by 419 · see citing works
Wu, W., Yu, L., Jiang, Q., Huo, M., Lin, H., Wang, L., Chen, Y., & Shi, J. (2019) · Journal of the American Chemical Society · doi:10.1021/jacs.9b03503 · Cited by 359 · see citing works
A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites
Johansson, B. (1992) · Acta Psychiatrica Scandinavica · doi:10.1111/j.1600-0447.1992.tb03310.x · Cited by 357 · 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
Association between oxidative stress and changes of trace elements in patients with breast cancer
Huang, Y., Sheu, J.-Y., & Lin, T. (1999) · Clinical Biochemistry · doi:10.1016/s0009-9120(98)00096-4 · Cited by 265 · see citing works
Kaviyarasu, K., Geetha, N., Kanimozhi, K., Magdalane, C. M., Sivaranjani, S., Ayeshamariam, A., Kennedy, J. V., & Mâaza, M. (2016) · Materials Science and Engineering C · doi:10.1016/j.msec.2016.12.024 · Cited by 261 · see citing works
The CDK inhibitors in cancer research and therapy
Cicenas, J., & Valius, M. (2011) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-011-1039-4 · Cited by 244 · see citing works
Allensworth, J. L., Evans, M. K., Bertucci, F., Aldrich, A. J., Festa, R. A., Finetti, P., Ueno, N. T., Safi, R., McDonnell, D. P., Thiele, D. J., et al. (2015) · Molecular Oncology · doi:10.1016/j.molonc.2015.02.007 · Cited by 243 · see citing works
Iljin, K., Ketola, K., Vainio, P., Halonen, P., Kohonen, P. J., Fey, V., Grafström, R. C., Perälä, M., & Kallioniemi, O. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-1035 · Cited by 242 · see citing works
Nechushtan, H., Hamamreh, Y., Nidal, S., Gotfried, M., Baron, A., Shalev, Y. I., Nisman, B., Peretz, T., & Peylan‐Ramu, N. (2015) · The Oncologist · doi:10.1634/theoncologist.2014-0424 · Cited by 204 · see citing works
Serum and Tissue Trace Metal Levels in Lung Cancer
Díez, M., Arroyo, M., Cerdán, F. J., Muñoz, M., Martín, M. A., & Balibrea, J. L. (2009) · Oncology · doi:10.1159/000226722 · Cited by 161 · see citing works
Chen, V. W., Ruiz, B. A., Hsieh, M., Wu, X., Ries, L. A. G., & Lewis, D. R. (2014) · Cancer · doi:10.1002/cncr.29045 · Cited by 158 · see citing works
Pipes and wiring: the regulation of copper uptake and distribution in yeast
Labbé, S., & Thiele, D. J. (1999) · Trends in Microbiology · doi:10.1016/s0966-842x(99)01638-8 · Cited by 121 · see citing works
Disulfiram’s anti-cancer activity reflects targeting NPL4, not inhibition of aldehyde dehydrogenase
Skrott, Z., Majera, D., Gursky, J., Buchtova, T., Hajduch, M., Mistrik, M., & Bartek, J. (2019) · Oncogene · doi:10.1038/s41388-019-0915-2 · Cited by 115 · see citing works
Collins, F. S. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3461 · Cited by 108 · see citing works
Peng, X., Pan, Q., Zhang, B., Wan, S., Li, S., Luo, K., Pu, Y., & He, B. (2019) · Biomacromolecules · doi:10.1021/acs.biomac.9b00367 · Cited by 107 · see citing works
Sodium ditiocarb as adjuvant immunotherapy for high risk breast cancer: A randomized study
Dufour, P., Lang, J.-M., Giron, C., Duclos, B., Haehnel, P., Jaeck, D., Jung, J. M., & Oberling, F. (1993) · Biotherapy · doi:10.1007/bf01877380 · Cited by 86 · see citing works
The cytotoxic mechanisms of disulfiram and copper(ii) in cancer cells
Tawari, P. E., Wang, Z., Najlah, M., Tsang, C. W., Kannappan, V., Liu, P., McConville, C., He, B., Armesilla, A. L., & Wang, W. (2015) · Toxicology Research · doi:10.1039/c5tx00210a · Cited by 86 · see citing works
Rajalakshmi, S., Weyhermüller, T., Dinesh, M. G., & Nair, B. U. (2012) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2012.08.010 · Cited by 79 · see citing works
Analytical Strategies for Assessment of Human Metabolites in Preclinical Safety Testing
Ma, S., & Chowdhury, S. K. (2011) · Analytical Chemistry · doi:10.1021/ac200349g · Cited by 71 · see citing works
Grossi, F., Kubota, K., Cappuzzo, F., de Marinis, F., Gridelli, C., Aita, M., & Douillard, J. (2010) · The Oncologist · doi:10.1634/theoncologist.2010-0322 · Cited by 70 · see citing works
Lung Cancer Staging: Clinical and Radiologic Perspectives
Chheang, S., & Brown, K. (2013) · Seminars in Interventional Radiology · doi:10.1055/s-0033-1342950 · Cited by 68 · see citing works
Wang, S., Hu, Y., Yu, Y., Cheng, Z., & Liu, T. (2018) · BMC Complementary and Alternative Medicine · doi:10.1186/s12906-018-2300-z · Cited by 40 · see citing works
Disulfiram neuropathy: Two cases of distal axonopathy
Filosto, M., Tentorio, M., Broglio, L., Buzio, S., Lazzarini, C., Pasolini, M. P., Cotelli, M. S., Scarpelli, M., Mancuso, M., Choub, A., et al. (2008) · Clinical Toxicology · doi:10.1080/15563650701636390 · Cited by 28 · see citing works
Zhong, Z., Mao, S., Lin, H., Li, H., Lin, J., & Lin, J. (2019) · Talanta · doi:10.1016/j.talanta.2019.05.088 · Cited by 26 · see citing works
Self-citationLi, M., kong, L. L., Gou, Y., Yang, F., & Liang, H. (2014) · Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy · doi:10.1016/j.saa.2014.02.197 · Cited by 23 · see citing works
Wang, S., Mao, S., Li, M., Li, H., & Lin, J. (2018) · Talanta · doi:10.1016/j.talanta.2018.08.016 · Cited by 22 · see citing works
Self-citationHassan, I., Khan, A. A., Aman, S., Qamar, W., Ebaid, H., Al‐Tamimi, J., Alhazza, I. M., & Rady, A. M. (2018) · Scientific Reports · doi:10.1038/s41598-018-19410-1 · Cited by 22 · see citing works
DNA Content, Cell Size, and Cell Senescence
Veitia, R. A. (2019) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2019.04.013 · Cited by 18 · see citing works
Liu, P., Brown, J. M., Channathodiyil, P., Kannappan, V., Armesilla, A. L., Darling, J. L., & Wang, W. (2013) · British Journal of Cancer · doi:10.1038/bjc.2013.19 · Cited by 15 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Lu, Y., Pan, Q., Gao, W., Pu, Y., & He, B. (2022) · Journal of Materials Chemistry B · doi:10.1039/d2tb01150f · Cited by 152 · see citing works
Lu, Y., Pan, Q., Gao, W., Pu, Y., Luo, K., He, B., & Gu, Z. (2022) · Biomaterials · doi:10.1016/j.biomaterials.2021.121335 · Cited by 149 · see citing works
Kannappan, V., Ali, M., Small, B., Rajendran, G., Elzhenni, S., Taj, H., Wang, W., & Dou, Q. P. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.741316 · Cited by 134 · see citing works
Hogarth, G., & Onwudiwe, D. C. (2021) · Inorganics · doi:10.3390/inorganics9090070 · Cited by 71 · see citing works
Disulfiram: A novel repurposed drug for cancer therapy
Min De, Z. E. N. G., Wu, B., Wei, W., Jiang, Z., Li, P., Quan, Y., & Hu, X. (2024) · Chinese Medical Journal · doi:10.1097/cm9.0000000000002909 · Cited by 64 · see citing works
Liu, Y., Guan, X., Wang, M., Wang, N., Chen, Y., Li, B., Xu, Z., Fu, F., Du, C., & Zheng, Z. (2022) · Bioengineered · doi:10.1080/21655979.2022.2038434 · Cited by 56 · see citing works
Cheng, Z., Gu, L., Zhao, Y., Yang, L., Chen, L., Wang, T., Luo, M., Wei, J., & Li, P. (2021) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2021.127555 · Cited by 45 · see citing works
Hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanocrystals for cancer therapy
Xiao, C., Li, J., Wang, X., Li, S., Xu, C., Zhang, Z., Hua, A., Ding, Z., Zhang, B., Yang, X., et al. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.02.043 · Cited by 32 · see citing works
Zhu, Y., Wang, N., Ling, J., Yang, L., Omer, A. M., Yang, G., & Yang, G. (2024) · Journal of Colloid and Interface Science · doi:10.1016/j.jcis.2024.01.121 · Cited by 26 · see citing works
Huang, Z., Luo, Y., Zhang, T., Ding, Y., Chen, M., Chen, J., Liu, Q., Huang, Y., & Zhao, C. (2022) · Angewandte Chemie International Edition · doi:10.1002/anie.202203500 · Cited by 24 · see citing works
Qing, L., Wang, T., Luo, H.-Y., Du, J.-L., Wang, R.-Y., & Luo, P. (2022) · TrAC Trends in Analytical Chemistry · doi:10.1016/j.trac.2022.116832 · Cited by 21 · see citing works
Cui, J., Li, W., Bu, W., Liu, J., Chen, X., Li, X., Liu, C., Meng, L., Chen, M., Sun, H., et al. (2022) · Biomaterials Advances · doi:10.1016/j.bioadv.2022.213038 · Cited by 17 · see citing works
A multifunctional drug delivery system based on switchable peptide-stabilized emulsions
Boas, D., van Teijlingen, A., Shpilt, Z., Shalev, D. E., Tshuva, E. Y., Tuttle, T., & Reches, M. (2024) · Chem · doi:10.1016/j.chempr.2024.02.003 · Cited by 15 · see citing works
Silva, C. M. F., Lino, R. C., de Moura, M. C. T., Borges, A. P. D. S., & Júnior, R. J. D. O. (2025) · Molecules · doi:10.3390/molecules30102104 · Cited by 14 · see citing works
Malakar, K., Selvakumaran, B., Murali, M., Prakash, P. A., Sangeetha, S., Sohtun, W. P., Jaabir, M. S. M., & Velusamy, M. (2023) · New Journal of Chemistry · doi:10.1039/d2nj06170h · Cited by 12 · see citing works
Wu, X., Wu, Q., Hou, M., Jiang, Y., Li, M., Jia, G., Yang, H., & Zhang, C. (2024) · Advanced Healthcare Materials · doi:10.1002/adhm.202401954 · Cited by 12 · see citing works
Mechanisms of Copper-Induced Autophagy and Links with Human Diseases
Fu, Y., Zeng, S., Wang, Z., Huang, H., Zhao, X., & Li, M. (2025) · Pharmaceuticals · doi:10.3390/ph18010099 · Cited by 8 · see citing works
Self-citationNon-invasive single cell aptasensing in live cells and animals
Osman, E. A., Rynes, T. P., Wang, Y., Mruk, K., & McKeague, M. (2024) · Chemical Science · doi:10.1039/d3sc05735f · Cited by 7 · see citing works
Self-citationLu, F., Wang, X., Xue, X., Liu, L. Z., Li, D., Liu, A. F., Qin, S., & Liu, L. (2026) · Cells · doi:10.3390/cells15060545 · Cited by 6 · see citing works
Huang, Z., Luo, Y., Zhang, T., Ding, Y., Chen, M., Chen, J., Liu, Q., Huang, Y., & Zhao, C. (2022) · Angewandte Chemie · doi:10.1002/ange.202203500 · Cited by 3 · see citing works
Macrophage pyroptosis inhibition alleviates postinjury neointimal formation and vascular restenosis
Ji, Z., He, M., Wu, H., Chen, S., Wang, S., Yin, X., & Wang, H. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-026-07777-z · 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
A Multifunctional Drug Delivery System Based on Switchable Peptide-Stabilized EmulsionsPreprint
Reches, M., Boas, D., van Teijlingen, A., Shpilt, Z., Shalev, D. E., Tshuva, E. Y., & Tuttle, T. (2023) · Research Square · doi:10.21203/rs.3.rs-3121613/v1 · Cited by 1 · see citing works
- Authors
- Lu, X., Lin, B., Xu, N., Huang, H., Wang, Y., & Lin, J.-M.
- Affiliations
- Tianjin University (CN)
- Tsinghua University (CN)
- Corresponding author
- Lin, Binxin
- Wang, Yong
- Lin, Jin-Ming
- ORCID
- Lin, Jin-Ming
- Venue
- Talanta
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 211
- Pages
- 120732
- ISSN
- 0039-9140 (ISSN-L)
- OpenAlex
- W3000004239
- Cited by
- 23
- References
- 38
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 5 · 2023: 3 · 2022: 6 · 2021: 4
- FWCI
- 1.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Talanta (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (21575100, 21621003, 21727814, 21922409)
- Tianjin Research Program of Application Foundation and Advanced Technology of China (17JCYBJC20500)
- Topics
- Health Sciences › Medicine › Oncology › Metal complexes synthesis and properties
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- disulfiram, copper complexes, A549 cells, drug repurposing, cancer therapy, intracellular accumulation, cell membrane permeability, reactive oxygen species, G0/G1 cell cycle arrest, apoptosis, cytotoxicity mechanism
- MeSH terms
- A549 Cells, Antineoplastic Agents, Cell Cycle, Copper, Ditiocarb, Disulfiram, Humans, Lung Neoplasms, Organometallic Compounds, Mass Spectrometry, Apoptosis, Cell Proliferation
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
