Disulfiram enhances the antitumor activity of cisplatin by inhibiting the Fanconi anemia repair pathway.

Meng Yuan; Qian WU; Mingyang Zhang; Minshan Lai; Wenbo Chen; Jianfeng Yang; Li Jiang; Ji Cao

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Disulfiram enhances the antitumor activity of cisplatin by inhibiting the Fanconi anemia repair pathway.

Author: Meng YUAN ¹ ; Qian WU ² ; Mingyang ZHANG ² ; Minshan LAI ² ; Wenbo CHEN ² ; Jianfeng YANG ³ ; Li JIANG ⁴ ; Ji CAO ⁵
Author Information

1. Laboratory of Fruit Quality Biology / the State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Fruit Science Institute, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou 310058, China.
2. Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
3. Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
4. The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310018, China. jiangli49@zju.edu.cn.
5. Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. caoji88@zju.edu.cn.
Publication Type:Journal Article
Keywords: Chemotherapy; Cisplatin (DDP); DNA damage; Disulfiram (DSF); Fanconi anemia (FA) repair
MeSH: Female; Male; Humans; Cisplatin/pharmacology*; Disulfiram/pharmacology*; Testicular Neoplasms/drug therapy*; Fanconi Anemia/drug therapy*; Alcoholism/drug therapy*; Drug Resistance, Neoplasm; Cell Line, Tumor; Substance Withdrawal Syndrome/drug therapy*; Apoptosis; Antineoplastic Agents/therapeutic use*; Cell Proliferation
From: Journal of Zhejiang University. Science. B 2023;24(3):207-220
CountryChina
Language:English
Abstract: A series of chemotherapeutic drugs that induce DNA damage, such as cisplatin (DDP), are standard clinical treatments for ovarian cancer, testicular cancer, and other diseases that lack effective targeted drug therapy. Drug resistance is one of the main factors limiting their application. Sensitizers can overcome the drug resistance of tumor cells, thereby enhancing the antitumor activity of chemotherapeutic drugs. In this study, we aimed to identify marketable drugs that could be potential chemotherapy sensitizers and explore the underlying mechanisms. We found that the alcohol withdrawal drug disulfiram (DSF) could significantly enhance the antitumor activity of DDP. JC-1 staining, propidium iodide (PI) staining, and western blotting confirmed that the combination of DSF and DDP could enhance the apoptosis of tumor cells. Subsequent RNA sequencing combined with Gene Set Enrichment Analysis (GSEA) pathway enrichment analysis and cell biology studies such as immunofluorescence suggested an underlying mechanism: DSF makes cells more vulnerable to DNA damage by inhibiting the Fanconi anemia (FA) repair pathway, exerting a sensitizing effect to DNA damaging agents including platinum chemotherapy drugs. Thus, our study illustrated the potential mechanism of action of DSF in enhancing the antitumor effect of DDP. This might provide an effective and safe solution for combating DDP resistance in clinical treatment.