Open Access

ARTICLE

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

by YAPING GAN^1,2,#, TING LIU^3,#, WEIFENG FENG^1,#, LIANG WANG⁴, LI LI⁵, YINGXIA NING^1,*

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

* Corresponding Author: YINGXIA NING. Email:
# These authors contributed equally to this work

(This article belongs to the Special Issue: Role of Reactive Oxygen Species and DNA Damage in Tumor Immunological Responses)

Oncology Research 2023, 31(3), 333-343. https://doi.org/10.32604/or.2023.028694

Received 02 January 2023; Accepted 22 March 2023; Issue published 22 May 2023

Abstract

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 B-cell 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.

---

Keywords

---