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.
Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
J Zhejiang Univ Sci B. 2023 Mar 15;24(3):207-220. doi: 10.1631/jzus.B2200405.
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.
一系列诱导 DNA 损伤的化疗药物，如顺铂（DDP），是治疗卵巢癌、睾丸癌和其他缺乏有效靶向药物治疗的疾病的标准临床治疗方法。耐药性是限制其应用的主要因素之一。增敏剂可以克服肿瘤细胞的耐药性，从而增强化疗药物的抗肿瘤活性。在这项研究中，我们旨在确定有市场潜力的药物，这些药物可能成为潜在的化疗增敏剂，并探索其潜在的机制。我们发现，酒精戒断药物双硫仑（DSF）可以显著增强 DDP 的抗肿瘤活性。JC-1 染色、碘化丙啶（PI）染色和 Western blot 证实，DSF 和 DDP 的联合使用可以增强肿瘤细胞的凋亡。随后的 RNA 测序结合基因集富集分析（GSEA）通路富集分析以及免疫荧光等细胞生物学研究表明，其潜在机制为：DSF 通过抑制范可尼贫血（FA）修复途径，使细胞对包括铂类化疗药物在内的 DNA 损伤剂更敏感，从而发挥增敏作用。因此，本研究阐明了 DSF 增强 DDP 抗肿瘤作用的潜在作用机制。这可能为临床治疗中克服 DDP 耐药性提供一种有效且安全的解决方案。
