《自然》12月14日卷文章：「治療酒精濫用藥物雙硫侖通過分離酶p97適配體NPL4作用於癌症」

12月14日出版的《自然》雜誌刊登的文章：「治療酒精濫用藥物雙硫侖通過分離酶p97適配體NPL4作用於癌症」（Alcohol-abuse drug disulfiram targets cancer

via p97 segregase adaptor NPL4 http://www.nature.com/articles/nature25016）文章摘要試譯如下：

癌症的發病率正在上升，這種全球性挑戰又因腫瘤對現有藥物的抗藥性進一步加劇。為改善癌症治療並滿足藥物的需求，藥物再利用是一種有希望的方法。在這裡，我們強調重新使用雙硫侖（disulfiram，商品名Antabuse）的可能性。這是一種使用很久的酒精排斥類藥物，已被證明在臨床前研究中對多種癌症類型有效。我們在全國的流行病學研究顯示，與那些在診斷（患癌）時停止使用雙硫侖的患者相比，繼續使用的患者死於癌症的風險要低。此外，我們鑒別了二硫卓銅複合物為雙硫侖的代謝物，具有抗癌作用；我們提供了發現腫瘤中該複合物優先累積和候選生物標誌物的檢測方法，以分析其對細胞和組織的影響。最後，我們的功能和生物物理學分析揭示，雙硫侖抑制腫瘤作用的分子靶標是NPL4。這是p97（也稱為VCP）分離酶的適配體。它對涉及細胞中多種調控和應激反應途徑的蛋白質周轉代謝是必需的。

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.

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