ArticleCells2020
Targeting the NPL4 Adaptor of p97/VCP Segregase by Disulfiram as an Emerging Cancer Vulnerability Evokes Replication Stress and DNA Damage while Silencing the ATR Pathway.
Article in Cells, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
27 citing papers in PubMed, 44 citations in OpenAlex.
- 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
- Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence.iScience · 2026Article
- A phase 1b open-label, dose-escalating study of safety and efficacy of disulfiram, copper and vinorelbine in advanced solid tumors.BMC cancer · 2026Article
- NPLOC4 Constructs Tumor Immunosuppressive Microenvironment in Pan-cancer and Hepatocellular Carcinoma.Current medicinal chemistry · 2026Article
- Bacterial hitchhiking with drug-loaded nanoparticles as a drug delivery strategy for cancer immunotherapy.npj biomedical innovations · 2025Article
- Disulfiram-Copper Potentiates Anticancer Efficacy of Standard Chemotherapy Drugs in Bladder Cancer Animal Model through ROS-Autophagy-Ferroptosis Signalling Cascade.Current cancer drug targets · 2025Article
- CuET overcomes regorafenib resistance by inhibiting epithelial-mesenchymal transition through suppression of the ERK pathway in hepatocellular carcinoma.Translational oncology · 2024Article
- Characterizing replisome disassembly in human cells.iScience · 2024Article
- Valosin-Containing Protein (VCP): A Review of Its Diverse Molecular Functions and Clinical Phenotypes.International journal of molecular sciences · 2024Review
- Polydopamine-Modified Copper Coordination Mesoporous Silica Nanoparticles Loaded with Disulfiram for Synergistic Chemo-Photothermal Therapy.Pharmaceutics · 2024Article
- Augmenting MEK inhibitor efficacy in BRAF wild-type melanoma: synergistic effects of disulfiram combination therapy.Journal of experimental & clinical cancer research : CR · 2024Article
- Dual-purposing disulfiram for enhanced chemotherapy and afterglow imaging using chlorin e6 and semiconducting polymer combined strategy.Theranostics · 2024Article
- NPLOC4 is a potential target and a poor prognostic signature in lung squamous cell carcinoma.Scientific reports · 2023Article
- Actionable cancer vulnerability due to translational arrest, p53 aggregation and ribosome biogenesis stress evoked by the disulfiram metabolite CuET.Cell death and differentiation · 2023Article
- The immunomodulatory function and antitumor effect of disulfiram: paving the way for novel cancer therapeutics.Discover oncology · 2023Review
- Advancing Cancer Therapy with Copper/Disulfiram Nanomedicines and Drug Delivery Systems.Pharmaceutics · 2023Review
- Disulfiram enhances the antitumor activity of cisplatin by inhibiting the Fanconi anemia repair pathway.Journal of Zhejiang University. Science. B · 2023Article
- The p97-Nploc4 ATPase complex plays a role in muscle atrophy during cancer and amyotrophic lateral sclerosis.Journal of cachexia, sarcopenia and muscle · 2022Article
- Disulfiram/copper induces antitumor activity against gastric cancer cells in vitro and in vivo by inhibiting S6K1 and c-Myc.Cancer chemotherapy and pharmacology · 2022Article
- Disulfiram/Copper induces antitumor activity against gastric cancer via the ROS/MAPK and NPL4 pathways.Bioengineered · 2022Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Research on repurposing the old alcohol-aversion drug disulfiram (DSF) for cancer treatment has identified inhibition of NPL4, an adaptor of the p97/VCP segregase essential for turnover of proteins involved in multiple pathways, as an unsuspected cancer cell vulnerability. While we reported that NPL4 is targeted by the anticancer metabolite of DSF, the bis-diethyldithiocarbamate-copper complex (CuET), the exact, apparently multifaceted mechanism(s) through which the CuET-induced aggregation of NPL4 kills cancer cells remains to be fully elucidated. Given the pronounced sensitivity to CuET in tumor cell lines lacking the genome integrity caretaker proteins BRCA1 and BRCA2, here we investigated the impact of NPL4 targeting by CuET on DNA replication dynamics and DNA damage response pathways in human cancer cell models. Our results show that CuET treatment interferes with DNA replication, slows down replication fork progression and causes accumulation of single-stranded DNA (ssDNA). Such a replication stress (RS) scenario is associated with DNA damage, preferentially in the S phase, and activates the homologous recombination (HR) DNA repair pathway. At the same time, we find that cellular responses to the CuET-triggered RS are seriously impaired due to concomitant malfunction of the ATRIP-ATR-CHK1 signaling pathway that reflects an unorthodox checkpoint silencing mode through ATR (Ataxia telangiectasia and Rad3 related) kinase sequestration within the CuET-evoked NPL4 protein aggregates.
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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.