Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 11, 78371 Olomouc, Czech Republic.
Mini Rev Med Chem. 2012 Oct;12(12):1184-92. doi: 10.2174/138955712802762068.
The idea of "repurposing" of existing drugs provides an effective way to develop and identify new therapies. Disulfiram (Antabuse), a drug commonly used for the treatment of alcoholism, shows promising anticancer activity in both preclinical and clinical studies. In the human body, disulfiram is rapidly converted to its reduced metabolite, diethyldithiocarbamate. If copper ions are available, a bis(diethyldithiocarbamate)-copper(II) complex is formed. Disulfiram's selective anticancer activity is attributed to the copper(II) complex's ability to inhibit the cellular proteasome. It is assumed that the complex inhibits the proteasome by a mechanism that is distinct to the clinically used drug bortezomib, targeting the 19S rather than the 20S proteasome. This difference could be explained by inhibition of the JAMM domain of the POH1 subunit within the lid of the 19S proteasome.
“重新利用”现有药物的想法为开发和鉴定新疗法提供了一种有效途径。双硫仑（安塔布司）是一种常用于治疗酗酒的药物，在临床前和临床研究中显示出有希望的抗癌活性。在人体内，双硫仑迅速转化为其还原代谢物二乙基二硫代氨基甲酸盐。如果有铜离子存在，就会形成双（二乙基二硫代氨基甲酸盐）-铜（II）配合物。双硫仑的选择性抗癌活性归因于铜（II）配合物抑制细胞蛋白酶体的能力。据推测，该配合物通过一种与临床上使用的药物硼替佐米不同的机制抑制蛋白酶体，靶向 19S 而不是 20S 蛋白酶体。这种差异可以通过抑制 19S 蛋白酶体盖中的 POH1 亚基的 JAMM 结构域来解释。
