Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to meet the need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (also known by the trade name Antabuse), an old alcohol-aversion drug that has been shown to be effective against diverse cancer types in preclinical studies. Our nationwide epidemiological study reveals that patients who continuously used disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. Moreover, we identify the ditiocarb–copper complex as the metabolite of disulfiram that is responsible for its anti-cancer effects, and provide methods to detect preferential accumulation of the complex in tumours and candidate biomarkers to analyse its effect on cells and tissues. Finally, our functional and biophysical analyses reveal the molecular target of disulfiram’s tumour-suppressing effects as NPL4, an adaptor of p97 (also known as VCP) segregase, which is essential for the turnover of proteins involved in multiple regulatory and stress-response pathways in cells.

中文翻译：

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酗酒药物双硫仑通过 p97 分离酶接头 NPL4 靶向癌症

癌症发病率正在上升，而肿瘤对现有药物的耐药性进一步加剧了这一全球性挑战。满足改进癌症治疗需求的一种有前景的方法是药物再利用。在这里，我们强调了重新利用双硫仑（也称为 Antabuse）的潜力，这是一种旧的酒精厌恶药物，在临床前研究中已被证明对多种癌症类型有效。我们的全国流行病学研究表明，与诊断时停止使用该药物的患者相比，持续使用双硫仑的患者死于癌症的风险较低。此外，我们将双硫威-铜复合物鉴定为双硫仑的代谢产物，负责其抗癌作用，并提供检测复合物在肿瘤中优先积累的方法和候选生物标志物，以分析其对细胞和组织的影响。最后，我们的功能和生物物理分析揭示了双硫仑的肿瘤抑制作用的分子靶标 NPL4，它是 p97（也称为 VCP）分离酶的接头，对于参与多种调节和应激反应途径的蛋白质的周转至关重要。细胞。