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Disulfiram/Copper Complex Induces Cytotoxicity in Pancreatic Cancer Cells and 5-Fluorouracil-Resistant Cells through
Eun Kyoung Kim1, Cheong Ran Je1, Sung Ill Jang1
1Division of Gastroenterology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
Background/Aims:
Pancreatic ductal adenocarcinoma (PDAC) is a challenging cancer to treat and has a poor prognosis and limited treatment options. In this study, the anticancer effects of disulfiram combined with copper (DSF/Cu) on PDAC cells, including those resistant to 5-fluorouracil, was assessed.
Methods:
Human pancreatic cancer cells (BxPC-3 and CFPAC-1) and their 5-fluorouracil-resistant (5FUR) counterparts were treated with DSF/Cu to assess cytotoxicity. Expression levels of nuclear factor E2-related factor-2 (NRF-2) and heme oxygenase-1 (HO-1) were analyzed by reverse transcription quantitative polymerase chain reaction and Western blotting, while intracellular reactive oxygen species (ROS) levels were evaluated using H2DCFDA staining and flow cytometry. The effects of DSF/Cu on protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) signaling pathways were evaluated by Western blot analysis. In vivo efficacy was investigated using a xenograft mouse model, in which mice were orally administered DSF (75 mg/kg) and Cu (2 mg/kg) twice weekly for 5 weeks.
Results:
We demonstrated that DSF/Cu effectively induced cytotoxicity in both pancreatic cancer cells and their 5FUR counterparts by modulating ROS levels, NRF-2 levels, and associated survival pathways. DSF/Cu treatment significantly decreased NRF-2 expression and reduced ROS levels, specifically in 5FUR cells. DSF/Cu facilitated NRF-2-independent HO-1 expression and differentially modulated Akt and MAPK signaling pathways in pancreatic cancer cells and their 5FUR counterparts. In vivo studies using a xenograft mouse model confirmed the antitumor efficacy of DSF/Cu, as evidenced by reduced tumor volumes and NRF-2 expression.
Conclusions:
These findings highlight the potential of DSF/Cu as a novel and effective therapeutic strategy for PDAC, specifically for overcoming resistance to standard therapies.
Insights
Disulfiram combined with copper (DSF/Cu) shows promise in treating pancreatic cancer, including drug-resistant forms. This novel therapy effectively reduces tumor growth by modulating key cellular pathways and reactive oxygen species levels.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) presents significant treatment challenges due to poor prognosis and limited therapeutic options.
- Investigating novel therapeutic strategies is crucial for improving outcomes in PDAC patients, particularly those with resistance to standard chemotherapy.
Purpose of the Study:
- To evaluate the anticancer effects of disulfiram combined with copper (DSF/Cu) on pancreatic cancer cells, including 5-fluorouracil-resistant (5FUR) PDAC.
- To elucidate the mechanisms underlying DSF/Cu's efficacy, focusing on reactive oxygen species (ROS), nuclear factor E2-related factor-2 (NRF-2), heme oxygenase-1 (HO-1), and key signaling pathways (Akt, MAPK).
Main Methods:
- Cytotoxicity assays were performed on human pancreatic cancer cell lines (BxPC-3, CFPAC-1) and their 5FUR-resistant counterparts treated with DSF/Cu.
- Gene and protein expression analysis (NRF-2, HO-1, Akt, MAPK) and ROS level assessment were conducted using RT-qPCR, Western blotting, and flow cytometry.
- Antitumor efficacy was evaluated in a xenograft mouse model treated with DSF/Cu.
Main Results:
- DSF/Cu induced significant cytotoxicity in both standard and 5FUR-resistant PDAC cells by modulating ROS levels and NRF-2 expression.
- DSF/Cu treatment decreased NRF-2 and ROS levels in 5FUR cells, while promoting NRF-2-independent HO-1 expression.
- The combination therapy differentially modulated Akt and MAPK signaling pathways and demonstrated significant antitumor efficacy in vivo, reducing tumor volume.
Conclusions:
- DSF/Cu exhibits potent anticancer activity against PDAC, including chemoresistant variants.
- The findings suggest DSF/Cu is a promising therapeutic strategy for overcoming resistance in PDAC treatment.
- DSF/Cu warrants further investigation as a novel treatment for pancreatic cancer.
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