Tetrathiomolybdate inhibits the reaction of cisplatin with human copper chaperone Atox1†,Metallomics

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Tetrathiomolybdate inhibits the reaction of cisplatin with human copper chaperone Atox1†
Metallomics ( IF 2.9 ) Pub Date : 2018-04-25 00:00:00 , DOI: 10.1039/c8mt00084k
Yao Tian _{1,

2,

3,

4,

5} , Tiantian Fang _{1,

2,

3,

4,

5} , Siming Yuan _{1,

2,

3,

4,

5} , Yuchuan Zheng _{2,

5,

6,

7} , Fabio Arnesano _{2,

8,

9,

10} , Giovanni Natile _{2,

8,

9,

10} , Yangzhong Liu _{1,

2,

3,

4,

5}

Affiliation

Cisplatin is a widely used anticancer drug in clinic, and ammonium tetrathiomolybdate ([(NH₄)₂MoS₄], TM) is a copper chelator used in clinic for the treatment of Wilson's disease. Recently, TM has been found to enhance the therapeutic effect of cisplatin; however, the origin of this effect is not clear. Here we found that TM can inhibit the reaction of cisplatin with Cu–Atox1 and prevent the protein unfolding and aggregation induced by cisplatin. Although Ag(I) binds to Atox1 in a way similar to Cu(I)–Atox1, TM does not prevent the reaction of Ag–Atox1 with cisplatin. This result indicates that the formation of a Mo-centered trimeric protein cluster in the TM–Cu–Atox1 system plays a role in the inhibitory effect. This work provides new insights into the mechanism by which TM enhances the cytotoxic efficacy of cisplatin and helps to circumvent cisplatin resistance of tumor cells.

中文翻译：

四硫代钼酸盐抑制顺铂与人类铜伴侣蛋白Atox1的反应†

顺铂是临床上广泛使用的抗癌药物，四硫代钼酸铵（[（NH ₄）₂ MoS ₄ ]，TM）是一种铜螯合剂，在临床上用于治疗威尔逊氏病。最近，已发现TM可以增强顺铂的治疗作用。但是，这种作用的起源尚不清楚。在这里，我们发现TM可以抑制顺铂与Cu–Atox1的反应，并防止顺铂诱导的蛋白质解折叠和聚集。尽管Ag（I）以类似于Cu（I）–Atox1，TM不会阻止Ag–Atox1与顺铂的反应。该结果表明，在TM–Cu–Atox1系统中以Mo为中心的三聚体蛋白簇的形成在抑制作用中起作用。这项工作为TM增强顺铂的细胞毒性功效并帮助规避肿瘤细胞对顺铂的耐药性提供了新的见解。

更新日期：2018-04-25

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