Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
Chem Soc Rev. 2020 Nov 21;49(22):8113-8136. doi: 10.1039/d0cs00259c. Epub 2020 Jun 29.
The endoplasmic reticulum (ER) has recently emerged as a promising target for anticancer agents. Cytotoxic compounds that target the ER often exhibit selectivity for cancer cells over non-cancer cells. Furthermore, the induction of ER stress often leads to immunogenic cell death, providing another factor that contributes to the clinical efficacy of drugs that target this organelle. Among potential ER stress-inducing agents, metal complexes, which possess redox activity and modular structures, have arisen as promising candidates. In the last two decades, dozens of metal complexes have been reported that kill cancer cells via ER stress induction, and many of these complexes exhibit nanomolar activity in vitro as well as powerful tumor inhibition in vivo. In this review, we summarize the current state of investigations on the ER stress-inducing properties of metal complexes. This review starts with a description of the ER, its function, and its role in cancer progression and treatment. Following this discussion, a guide to experimental methods that can be used by researchers to detect ER stress is provided. The majority of this review summarizes previous studies on metal-based anticancer agents that cause ER stress. Finally, a discussion on the perspectives and significance of using metal complexes as ER stress-inducing agents for the treatment of cancer is provided, along with a summary of structural trends that contribute to this type of biological activity.
内质网（ER）最近成为抗癌药物的一个有前途的靶点。靶向 ER 的细胞毒性化合物通常对癌细胞具有选择性，而对非癌细胞则没有。此外，内质网应激的诱导往往导致免疫原性细胞死亡，这为靶向该细胞器的药物的临床疗效提供了另一个因素。在潜在的内质网应激诱导剂中，具有氧化还原活性和模块化结构的金属配合物已成为有前途的候选物。在过去的二十年中，已经报道了数十种通过诱导内质网应激杀死癌细胞的金属配合物，其中许多配合物在体外具有纳摩尔级的活性，并且在体内具有强大的肿瘤抑制作用。在这篇综述中，我们总结了金属配合物诱导内质网应激特性的研究现状。这篇综述首先描述了内质网的结构、功能及其在癌症进展和治疗中的作用。在讨论之后，提供了研究人员用于检测内质网应激的实验方法指南。本篇综述的大部分内容总结了以前关于导致内质网应激的基于金属的抗癌剂的研究。最后，讨论了将金属配合物作为诱导内质网应激的试剂用于癌症治疗的观点和意义，并总结了有助于这种类型的生物学活性的结构趋势。
