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.
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。
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Acknowledgments
The work was supported by the National Natural Science Foundation of China (No. 82104192), the Zhejiang Provincial Natural Science Foundation (No. LR22H310002), the Scientific Research Fund of Zhejiang University (No. XY2021044), and the Zhejiang University K. P. Chao’s High Technology Development Foundation.
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Meng YUAN, Qian WU, Mingyang ZHANG, Minshan LAI, and Wenbo CHEN performed the experimental research and data analysis. Meng YUAN, Qian WU, and Minshan LAI wrote and edited the manuscript. Jianfeng YANG, Li JIANG, and Ji CAO contributed to the study design, writing, and editing of the manuscript. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.
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Meng YUAN, Qian WU, Mingyang ZHANG, Minshan LAI, Wenbo CHEN, Jianfeng YANG, Li JIANG, and Ji CAO declare that they have no conflict of interest.
This article does not contain any studies with human or animal subjects performed by any of the authors.
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Yuan, M., Wu, Q., Zhang, M. et al. Disulfiram enhances the antitumor activity of cisplatin by inhibiting the Fanconi anemia repair pathway. J. Zhejiang Univ. Sci. B 24, 207–220 (2023). https://doi.org/10.1631/jzus.B2200405
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DOI: https://doi.org/10.1631/jzus.B2200405