Eun Kyoung Kim, Cheong Ran Je, Sung Ill Jang, Jung Hyun Jo, See Young Lee, Young Ju Lee, Jae Hee Cho
{"title":"双硫仑/铜复合物通过抑制核因子e2相关因子2和活性氧调节诱导胰腺癌细胞和5-氟尿嘧啶耐药细胞的细胞毒性","authors":"Eun Kyoung Kim, Cheong Ran Je, Sung Ill Jang, Jung Hyun Jo, See Young Lee, Young Ju Lee, Jae Hee Cho","doi":"10.5009/gnl250028","DOIUrl":null,"url":null,"abstract":"<p><strong>Background/aims: </strong>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.</p><p><strong>Methods: </strong>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. <i>In vivo</i> 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.</p><p><strong>Results: </strong>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. <i>In vivo</i> studies using a xenograft mouse model confirmed the antitumor efficacy of DSF/Cu, as evidenced by reduced tumor volumes and NRF-2 expression.</p><p><strong>Conclusions: </strong>These findings highlight the potential of DSF/Cu as a novel and effective therapeutic strategy for PDAC, specifically for overcoming resistance to standard therapies.</p>","PeriodicalId":12885,"journal":{"name":"Gut and Liver","volume":" ","pages":""},"PeriodicalIF":3.4000,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Disulfiram/Copper Complex Induces Cytotoxicity in Pancreatic Cancer Cells and 5-Fluorouracil-Resistant Cells through Nuclear Factor E2-Related Factor-2 Suppression and Reactive Oxygen Species Modulation.\",\"authors\":\"Eun Kyoung Kim, Cheong Ran Je, Sung Ill Jang, Jung Hyun Jo, See Young Lee, Young Ju Lee, Jae Hee Cho\",\"doi\":\"10.5009/gnl250028\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background/aims: </strong>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.</p><p><strong>Methods: </strong>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. <i>In vivo</i> 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.</p><p><strong>Results: </strong>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. <i>In vivo</i> studies using a xenograft mouse model confirmed the antitumor efficacy of DSF/Cu, as evidenced by reduced tumor volumes and NRF-2 expression.</p><p><strong>Conclusions: </strong>These findings highlight the potential of DSF/Cu as a novel and effective therapeutic strategy for PDAC, specifically for overcoming resistance to standard therapies.</p>\",\"PeriodicalId\":12885,\"journal\":{\"name\":\"Gut and Liver\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.4000,\"publicationDate\":\"2025-07-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Gut and Liver\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.5009/gnl250028\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Gut and Liver","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.5009/gnl250028","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
Disulfiram/Copper Complex Induces Cytotoxicity in Pancreatic Cancer Cells and 5-Fluorouracil-Resistant Cells through Nuclear Factor E2-Related Factor-2 Suppression and Reactive Oxygen Species Modulation.
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.
期刊介绍：
Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut and Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology.
Gut and Liver is jointly owned and operated by 8 affiliated societies in the field of gastroenterology, namely: the Korean Society of Gastroenterology, the Korean Society of Gastrointestinal Endoscopy, the Korean Society of Neurogastroenterology and Motility, the Korean College of Helicobacter and Upper Gastrointestinal Research, the Korean Association for the Study of Intestinal Diseases, the Korean Association for the Study of the Liver, the Korean Pancreatobiliary Association, and the Korean Society of Gastrointestinal Cancer.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
