Journal of Zhejiang University

Journal of Zhejiang University SCIENCE B

Accepted manuscript available online (unedited version)

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

Author(s): Meng YUAN, Qian WU, Mingyang ZHANG, Minshan LAI, Wenbo CHEN, Jianfeng YANG, Li JIANG, Ji CAO
Affiliation(s): 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; more
Corresponding email(s): caoji88@zju.edu.cn, jiangli49@zju.edu.cn
Key Words: Disulfiram (DSF); Cisplatin (DDP); DNA damage; Fanconi anemia (FA) repair; Chemotherapy

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Meng YUAN, Qian WU, Mingyang ZHANG, Minshan LAI, Wenbo CHEN, Jianfeng YANG, Li JIANG, Ji CAO. Disulfiram enhances the antitumor activity of cisplatin by inhibiting the Fanconi anemia repair pathway[J]. Journal of Zhejiang University Science B,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.B2200405

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author="Meng YUAN, Qian WU, Mingyang ZHANG, Minshan LAI, Wenbo CHEN, Jianfeng YANG, Li JIANG, Ji CAO",
journal="Journal of Zhejiang University Science B",
year="in press",
publisher="Zhejiang University Press & Springer",
doi="https://doi.org/10.1631/jzus.B2200405"
}

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%T Disulfiram enhances the antitumor activity of cisplatin by inhibiting the Fanconi anemia repair pathway
%A Meng YUAN
%A Qian WU
%A Mingyang ZHANG
%A Minshan LAI
%A Wenbo CHEN
%A Jianfeng YANG
%A Li JIANG
%A Ji CAO
%J Journal of Zhejiang University SCIENCE B
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doi="https://doi.org/10.1631/jzus.B2200405"

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T1 - Disulfiram enhances the antitumor activity of cisplatin by inhibiting the Fanconi anemia repair pathway
A1 - Meng YUAN
A1 - Qian WU
A1 - Mingyang ZHANG
A1 - Minshan LAI
A1 - Wenbo CHEN
A1 - Jianfeng YANG
A1 - Li JIANG
A1 - Ji CAO
J0 - Journal of Zhejiang University Science B
SP - 207
EP - 220
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Y1 - in press
PB - Zhejiang University Press & Springer
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doi="https://doi.org/10.1631/jzus.B2200405"

Abstract
Chinese Summary
Academic Network
Reviewer Comment

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.

双硫仑通过抑制范可尼贫血修复途径增加顺铂的抗肿瘤活性

袁梦¹，吴倩²，张明炀²，赖泯汕^2,3，陈文博^2,3，杨建锋^4,5，蒋莉⁶，曹戟^2,6,7
¹浙江大学农业与生物技术学院，果实品质生物实验室 / 农业部园艺作物生长发育与品质调实验室，中国杭州市，310058
²浙江大学药学院，浙江省抗癌药物研究重点实验室药理毒理研究所，中国杭州市，310058
³浙江大学工程师学院，中国杭州市，310015
⁴浙江大学医学院附属杭州市第一人民医院，消化内科，中国杭州市，310006
⁵浙江省胆胰疾病中西医结合重点实验室，中国杭州市，310006
⁶浙江大学智能创新药物研究院，中国杭州市，310018
⁷浙江大学癌症研究院，中国杭州市，310058
概要：由于缺乏有效的靶向药物，顺铂（DDP）等一系列DNA损伤诱导剂一直是卵巢癌、睾丸癌等恶性肿瘤的重要临床治疗药物。然而，临床上出现的耐药性是限制该类药物应用的主要因素之一。药物增敏剂可以克服肿瘤细胞耐药性，从而增强化疗药物的抗肿瘤活性。在本研究中，我们旨在从上市药物中发现潜在的化疗药物增敏剂，并探索其潜在的作用机制。通过系统筛选，我们发现戒酒药物双硫仑（DSF）可以增强DDP的抗肿瘤活性。通过JC-1染色、碘化丙啶（PI）染色和蛋白质印迹等实验证实DSF和DDP的合用可协同促进肿瘤细胞发生凋亡。通过RNA测序结合基因富集分析（GSEA）以及免疫荧光等细胞生物学实验，我们发现DSF协同DDP抗肿瘤作用的潜在分子机制：DSF通过抑制范可尼贫血（FA）修复途径使肿瘤细胞更容易发生DNA损伤，因此可对包括铂类化疗药物在内的引起DNA损伤的药物产生增敏作用。我们的这项研究揭示了DSF在增强DDP抗肿瘤作用方面的潜在机制，为临床治疗中的DDP耐药提供了一种潜在的安全有效的解决方案。

关键词组：双硫仑；顺铂；DNA损伤；范可尼贫血（FA）修复；化疗

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

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