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Targeting Esophageal Squamous Cell Carcinoma by Combining Copper Ionophore Disulfiram and JMJD3/UTX Inhibitor GSK J4
Canlin Yang1,2, Fei Li1, Yuanyuan Ren1
1Department of Oncology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou 225300, China.
Abstract:
The alcohol-averse drug disulfiram has been reported to have anti-tumor effects and is well suited for drug combinations. In order to identify potential drug combinations in esophageal squamous cell carcinoma (ESCC), we screened a bioactive compound library with the disulfiram copper chelation product CuET. The Jumonji domain-containing protein 3 (JMJD3) and the ubiquitously transcribed tetratricopeptide repeat protein X-linked (UTX) inhibitor GSK J4 were identified. To further understand the molecular mechanism underlying the efficient drug combination, we applied quantitative mass spectrometry to analyze the signaling pathway perturbation after drug treatment. The data revealed that the synergistic effect of GSK J4 and CuET was due to the interaction among JMJD3 and UTX, which may play important roles in maintaining endoplasmic reticulum (ER) homeostasis in tumor cells. Interestingly, our clinical data analysis showed that high expression of JMJD3 and UTX was associated with T stage and worse prognosis of ESCC patients, further supporting the importance of the above findings. In conclusion, our findings suggest that the combination of CuET and targeting JMJD3/UTX may be a safe, effective, and available treatment for ESCC.
Insights
Disulfiram derivative CuET combined with GSK J4 shows promise for esophageal cancer treatment. This combination targets JMJD3 and UTX proteins, potentially improving endoplasmic reticulum homeostasis and patient prognosis.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Disulfiram exhibits anti-tumor properties and is suitable for drug combinations.
- Esophageal squamous cell carcinoma (ESCC) requires novel therapeutic strategies.
Purpose of the Study:
- To identify effective drug combinations for ESCC using disulfiram.
- To elucidate the molecular mechanisms of synergistic drug effects in ESCC.
Main Methods:
- Screening a bioactive compound library with disulfiram copper chelation product (CuET).
- Identifying inhibitors of Jumonji domain-containing protein 3 (JMJD3) and ubiquitously transcribed tetratricopeptide repeat protein X-linked (UTX).
- Utilizing quantitative mass spectrometry to analyze signaling pathway perturbations.
Main Results:
- GSK J4, an inhibitor of JMJD3 and UTX, was identified as a potential combination partner for CuET.
- Synergistic effects of GSK J4 and CuET involve interactions between JMJD3 and UTX, impacting endoplasmic reticulum homeostasis.
- High expression of JMJD3 and UTX correlates with advanced T stage and poorer prognosis in ESCC patients.
Conclusions:
- The combination of CuET and targeting JMJD3/UTX presents a potential therapeutic strategy for ESCC.
- This approach may offer a safe, effective, and readily available treatment option for esophageal squamous cell carcinoma.
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