Denoyer Delphine, Clatworthy Sharnel A S, Cater Michael A
Met Ions Life Sci. 2018 Feb 5;18. doi: 10.1515/9783110470734-022.
Copper homeostasis is tightly regulated in both prokaryotic and eukaryotic cells to ensure sufficient amounts for cuproprotein biosynthesis, while limiting oxidative stress production and toxicity. Over the last century, copper complexes have been developed as antimicrobials and for treating diseases involving copper dyshomeostasis (e.g., Wilson's disease). There now exists a repertoire of copper complexes that can regulate bodily copper through a myriad of mechanisms. Furthermore, many copper complexes are now being appraised for a variety of therapeutic indications (e.g., Alzheimer's disease and amyotrophic lateral sclerosis) that require a range of copper-related pharmacological affects. Cancer therapy is also drawing considerable attention since copper has been recognized as a limiting factor for multiple aspects of cancer progression including growth, angiogenesis, and metastasis. Consequently, 'old copper complexes' (e.g., tetrathiomolybdate and clioquinol) have been repurposed for cancer therapy and have demonstrated anticancer activity in vitro and in preclinical models. Likewise, new tailor-made copper complexes have been designed based on structural and biological features ideal for their anticancer activity. Human clinical trials continue to evaluate the therapeutic efficacy of copper complexes as anticancer agents and considerable progress has been made in understanding their pharmacological requirements. In this chapter, we present a historical perspective on the main copper complexes that are currently being repurposed for cancer therapy and detail several of the more recently developed compounds that have emerged as promising anticancer agents. We further provide an overview of the known mechanisms of action, including molecular targets and we discuss associated clinical trials.
在原核细胞和真核细胞中，铜稳态都受到严格调控，以确保有足够的铜用于铜蛋白生物合成，同时限制氧化应激的产生和毒性。在过去的一个世纪里，铜配合物已被开发用作抗菌剂，并用于治疗涉及铜稳态失衡的疾病（如威尔逊氏病）。现在有一系列铜配合物可以通过多种机制调节体内的铜。此外，许多铜配合物目前正在针对各种治疗适应症（如阿尔茨海默病和肌萎缩侧索硬化症）进行评估，这些适应症需要一系列与铜相关的药理作用。癌症治疗也备受关注，因为铜已被认为是癌症进展多个方面（包括生长、血管生成和转移）的限制因素。因此，“旧的铜配合物”（如四硫代钼酸盐和氯碘羟喹）已被重新用于癌症治疗，并在体外和临床前模型中显示出抗癌活性。同样，基于对其抗癌活性理想的结构和生物学特性，设计了新的定制铜配合物。人体临床试验继续评估铜配合物作为抗癌药物的治疗效果，并且在了解其药理需求方面已经取得了相当大的进展。在本章中，我们将对目前正被重新用于癌症治疗的主要铜配合物进行历史回顾，并详细介绍几种最近开发的、已成为有前景的抗癌药物的化合物。我们还将概述已知的作用机制，包括分子靶点，并讨论相关的临床试验。
