Departments of Oncology, Pharmacology & Pathology, School of Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, United States.
Recent Pat Anticancer Drug Discov. 2019;14(2):113-132. doi: 10.2174/1574892814666190514104035.
Despite years of success of most anti-cancer drugs, one of the major clinical problems is inherent and acquired resistance to these drugs. Overcoming the drug resistance or developing new drugs would offer promising strategies in cancer treatment. Disulfiram, a drug currently used in the treatment of chronic alcoholism, has been found to have anti-cancer activity.
To summarize the anti-cancer effects of Disulfiram through a thorough patent review.
This article reviews molecular mechanisms and recent patents of Disulfiram in cancer therapy.
Several anti-cancer mechanisms of Disulfiram have been proposed, including triggering oxidative stress by the generation of reactive oxygen species, inhibition of the superoxide dismutase activity, suppression of the ubiquitin-proteasome system, and activation of the mitogen-activated protein kinase pathway. In addition, Disulfiram can reverse the resistance to chemotherapeutic drugs by inhibiting the P-glycoprotein multidrug efflux pump and suppressing the activation of NF-kB, both of which play an important role in the development of drug resistance. Furthermore, Disulfiram has been found to reduce angiogenesis because of its metal chelating properties as well as its ability to inactivate Cu/Zn superoxide dismutase and matrix metalloproteinases. Disulfiram has also been shown to inhibit the proteasomes, DNA topoisomerases, DNA methyltransferase, glutathione S-transferase P1, and O6- methylguanine DNA methyltransferase, a DNA repair protein highly expressed in brain tumors. The patents described in this review demonstrate that Disulfiram is useful as an anti-cancer drug.
For years the FDA-approved, well-tolerated, inexpensive, orally-administered drug Disulfiram was used in the treatment of chronic alcoholism, but it has recently demonstrated anti-cancer effects in a range of solid and hematological malignancies. Its combination with copper at clinically relevant concentrations might overcome the resistance of many anti-cancer drugs in vitro, in vivo, and in patients.
尽管大多数抗癌药物已经取得了多年的成功，但其中一个主要的临床问题是这些药物存在固有和获得性耐药性。克服耐药性或开发新药物将为癌症治疗提供有前途的策略。二硫化物，一种目前用于治疗慢性酒精中毒的药物，已被发现具有抗癌活性。
通过全面的专利审查总结二硫化物的抗癌作用。
本文综述了二硫化物在癌症治疗中的分子机制和最新专利。
已经提出了几种二硫化物的抗癌机制，包括通过产生活性氧物种引发氧化应激、抑制超氧化物歧化酶活性、抑制泛素-蛋白酶体系统以及激活丝裂原活化蛋白激酶途径。此外，二硫化物通过抑制 P-糖蛋白多药外排泵和抑制 NF-kB 的激活来逆转化疗药物的耐药性，这两者在耐药性的发展中都起着重要作用。此外，二硫化物已被发现因其金属螯合特性以及失活 Cu/Zn 超氧化物歧化酶和基质金属蛋白酶的能力而减少血管生成。二硫化物还被证明可以抑制蛋白酶体、DNA 拓扑异构酶、DNA 甲基转移酶、谷胱甘肽 S-转移酶 P1 和 O6-甲基鸟嘌呤 DNA 甲基转移酶，这是一种在脑肿瘤中高度表达的 DNA 修复蛋白。本综述中描述的专利表明，二硫化物可用作抗癌药物。
多年来，美国食品和药物管理局批准的、耐受性良好的、廉价的、口服给予的二硫化物用于治疗慢性酒精中毒，但最近在一系列实体瘤和血液系统恶性肿瘤中显示出抗癌作用。其与临床相关浓度的铜结合可能会克服许多抗癌药物在体外、体内和患者中的耐药性。
