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Drug repositioning of disulfiram induces endometrioid epithelial ovarian cancer cell death via the both apoptosis and cuproptosis pathways

查看全文 作　　者：YAPING [1,2]GAN;TING [3]LIU;WEIFENG [1]FENG;LIANG [4]WANG;LI [5]LI;YINGXIA [1]NING 高影响力作者 机构地区：[1]Department of Gynaecology and Obstetrics,The First Affiliated Hospital of Jinan University,Guangzhou,China;[2]Department of Gynaecology and Obstetrics,The First Affiliated Hospital of Guangzhou Medical University,Guangzhou,China;[3]Department of Anesthesiology,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai,China;[4]Guangdong Guojian Pharmaceutical Consulting Co.,Ltd.,Guangzhou,China;[5]Department of Galactophore Surgery,The Second Affiliated Hospital of Nanchang University,Nanchang,China高影响力机构 出　　处：《Oncology Research》索引2023年第31卷第3期,共11页高影响力期刊 基　　金：funded by Guangzhou Scienceand Information Bureau Item of China(Grant No.201904010013);by Natural Science Foundation of Guangdong Province of China(Grant No.2018A0303130180). 摘　　要：Various therapeutic strategies have been developed to overcome ovarian cancer.However,the prognoses resulting from these strategies are still unclear.In the present work,we screened 54 small molecule compounds approved by the FDA to identify novel agents that could inhibit the viability of human epithelial ovarian cancer cells.Among these,we identified disulfiram(DSF),an old alcohol-abuse drug,as a potential inducer of cell death in ovarian cancer.Mechanistically,DSF treatment significantly reduced the expression of the anti-apoptosis marker Bcell lymphoma/leukemia-2(Bcl-2)and increase the expression of the apoptotic molecules Bcl2 associated X(Bax)and cleaved caspase-3 to promote human epithelial ovarian cancer cell apoptosis.Furthermore,DSF is a newly identified effective copper ionophore,thus the combination of DSF and copper was used to reduce ovarian cancer viability than DSF single treatment.Combination treatment with DSF and copper also led to the reduced expression of ferredoxin 1 and loss of Fe-S cluster proteins(biomarkers of cuproptosis).In vivo,DSF and copper gluconate significantly decreased the tumor volume and increased the survival rate in a murine ovarian cancer xenograft model.Thus,the role of DSF revealed its potential for used as a viable therapeutic agent for the ovarian cancer. 关 键 词：Ovarian cancer Drug repositioning DISULFIRAM APOPTOSIS Cuproptosis
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