Targeting Ubiquitin-Proteasome System With Copper Complexes for Cancer Therapy.

Characterizing mechanisms of protein homeostasis, a process of balancing between protein synthesis and protein degradation, is important for understanding the potential causes of human diseases. The ubiquitin–proteasome system (UPS) is a well-studied mechanism of protein catabolism, which is responsible for eliminating misfolded, damaged, or aging proteins, thereby maintaining quality and quantity of cellular proteins. The UPS is composed of multiple components, including a series of enzymes (E1, E2, E3, and deubiquitinase [DUB]) and 26S proteasome (19S regulatory particles + 20S core particle). An impaired UPS pathway is involved in multiple diseases, including cancer. Several proteasome inhibitors, such as bortezomib, carfilzomib, and ixazomib, are approved to treat patients with certain cancers. However, their applications are limited by side effects, drug resistance, and drug–drug interactions observed in their clinical processes. To overcome these shortcomings, alternative UPS inhibitors have been searched for in many fields. Copper complexes (e.g., CuET, CuHQ, CuCQ, CuPDTC, CuPT, and CuHK) are found to be able to inhibit a core component of the UPS machinery, such as 20S proteasome, 19S DUBs, and NPLOC4/NPL4 complex, and are proposed to be one class of metal-based anticancer drugs. In this review, we will summarize functions and applications of copper complexes in a concise perspective, with a focus on connections between the UPS and cancer.

蛋白质稳态是蛋白质合成与蛋白质降解之间的一种平衡过程，对其机制进行表征对于理解人类疾病的潜在病因非常重要。泛素 - 蛋白酶体系统（UPS）是一种经过充分研究的蛋白质分解代谢机制，它负责清除错误折叠、受损或老化的蛋白质，从而维持细胞内蛋白质的质量和数量。UPS由多个组分组成，包括一系列酶（E1、E2、E3和去泛素化酶[DUB]）以及26S蛋白酶体（19S调节颗粒 + 20S核心颗粒）。UPS通路受损涉及多种疾病，包括癌症。几种蛋白酶体抑制剂，如硼替佐米、卡非佐米和伊沙佐米，已被批准用于治疗某些癌症患者。然而，它们在临床应用过程中受到副作用、耐药性以及药物 - 药物相互作用的限制。为了克服这些缺点，许多领域都在寻找替代的UPS抑制剂。研究发现铜配合物（例如，CuET、CuHQ、CuCQ、CuPDTC、CuPT和CuHK）能够抑制UPS机制的核心组分，如20S蛋白酶体、19S去泛素化酶和NPLOC4/NPL4复合物，并被提议作为一类金属基抗癌药物。在这篇综述中，我们将从简洁的角度总结铜配合物的功能和应用，重点关注UPS与癌症之间的联系。