In:
Anti-Cancer Agents in Medicinal Chemistry, Bentham Science Publishers Ltd., Vol. 23, No. 15 ( 2023-09), p. 1754-1764
Abstract:
Among gynecological cancers, ovarian cancer has a high mortality rate. Cisplatin-based
chemotherapy is commonly used for the treatment of ovarian cancer. However, the clinical efficacy of cisplatin in ovarian cancer is limited due to the development of chemo-resistance during treatment. Objective: In the study, we aimed to investigate the synergistic anti-cancer activity and targets of the FDA-approved
drug disulfiram combined with cisplatin in ovarian cancer. Methods: The cell viability was determined by Celltier-Glo luminescent assay. The synergistic anti-cancer activity was
assessed by combination index. Cell cycle and apoptosis were detected by flow cytometry. The in vivo anti-tumor activity and side effects were evaluated using a xenografted mice model. The synergistic anti-cancer targets were identified
by a mass spectrometry-based proteomics analysis. Results: In this study, we first found that disulfiram synergistically enhanced the anti-tumor activity of cisplatin in
chemo-resistant ovarian cancer cells, which was accompanied by the enhanced induction of cellular apoptosis. Secondly, the in vivo study demonstrated that the combination treatment of disulfiram and cisplatin dramatically
inhibited tumor growth and had no apparent side effects in ovarian cancer xenografted mice. Finally, proteomics analysis identified SMAD3 as a potential target of disulfiram-cisplatin combined treatment, and the down-regulation of
SMAD3 could increase cisplatin-induced cell death in ovarian cancer. Conclusion: Combination treatment of disulfiram and cisplatin synergistically inhibited the growth of ovarian cancer
through down-regulating SMAD3. As a repurposed drug, disulfiram could be quickly transformed into a clinic to overcome cisplatin resistance for the treatment of ovarian cancer.
Type of Medium:
Online Resource
ISSN:
1871-5206
DOI:
10.2174/1871520623666230516161200
Language:
English
Publisher:
Bentham Science Publishers Ltd.
Publication Date:
2023
SSG:
15,3
