Disulfiram, and disulfiram derivatives as novel potential anticancer drugs targeting the ubiquitin-proteasome system in both preclinical and clinical studies.
Disulfiram, and disulfiram derivatives as novel potential anticancer drugs targeting the ubiquitin-proteasome system in both preclinical and clinical studies.
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DOI：
10.2174/156800911794519798
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发表时间：
2011-02
影响因子：
3
通讯作者：
F. Kona;D. Buac;A. M Burger
中科院分区：
文献类型：
--
作者：
F. Kona;D. Buac;A. M Burger
双硫仑是 FDA 批准的治疗酒精中毒的药物，已有 5 多年的临床应用历史。尽管 20 世纪 70 年代和 80 年代的数据表明双硫仑及其类似物能够增强抗癌细胞毒性药物的活性，并且可能是有用的化学预防剂，但直到最近，其潜在的分子机制仍然未知。对可抑制蛋白酶体并用作新型抗癌药物的药物的大规模筛选工作表明，双硫仑具有蛋白酶体抑制活性。此外，双硫仑还被发现对锌指和环指泛素 E3 连接酶具有特异性活性，而锌指和环指泛素 E3 连接酶在癌症发展中发挥着重要作用。在这里，我们回顾了探索双硫仑作为抗癌药物的临床前和临床研究，以及专注于开发双硫仑衍生物作为泛素-蛋白酶体系统抑制剂的研究项目。
Disulfiram is a FDA approved drug for the treatment of alcoholism and available for clinical use since over 5 decades. Despite data from the 1970s and 80s that showed that disulfiram and analogs are able to enhance the activity of anticancer cytotoxic drugs and might be useful chemopreventative agents, the underlying molecular mechanisms remained unknown until recently. Large scale screening efforts for agents that can inhibit the proteasome and be used as novel anticancer drugs, revealed that disulfiram has proteasome inhibitory activity. Moreover, disulfiram was also found to have specific activity against zinc fingers and RING-finger ubiquitin E3 ligases that play an important role in cancer development. Here, we review the preclinical and clinical studies exploring disulfiram as an anticancer agent as well as research programs that focus on the development of disulfiram derivatives as inhibitors of the ubiquitin-proteasome system.