Jayaweera Shansa Pranami E, Wanigasinghe Kanakanamge Sacheela Prasadi, Rajalingam Dharshika, Silva Gayathri N
Department of Chemistry, Faculty of Science, University of Colombo, Colombo, Sri Lanka.
Front Oncol. 2021 Nov 10;11:740796. doi: 10.3389/fonc.2021.740796. eCollection 2021.
The proteasome is crucial for the degradation of intracellular proteins and plays an important role in mediating a number of cell survival and progression events by controlling the levels of key regulatory proteins such as cyclins and caspases in both normal and tumor cells. However, compared to normal cells, cancer cells are more dependent on the ubiquitin proteasome pathway (UPP) due to the accumulation of proteins in response to uncontrolled gene transcription, allowing proteasome to become a potent therapeutic target for human cancers such as multiple myeloma (MM). Up to date, three proteasome inhibitors namely bortezomib (2003), carfilzomib (2012) and ixazomib (2015) have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with relapsed and/or refractory MM. This review mainly focuses on the biochemical properties, mechanism of action, toxicity profile and pivotal clinical trials related to carfilzomib, a second-generation proteasome inhibitor that binds irreversibly with proteasome to overcome the major toxicities and resistance associated with bortezomib.
蛋白酶体对于细胞内蛋白质的降解至关重要，并且在通过控制正常细胞和肿瘤细胞中关键调节蛋白（如细胞周期蛋白和半胱天冬酶）的水平来介导许多细胞存活和进展事件中发挥重要作用。然而，与正常细胞相比，癌细胞由于响应不受控制的基因转录而积累蛋白质，因此对泛素蛋白酶体途径（UPP）的依赖性更强，这使得蛋白酶体成为多发性骨髓瘤（MM）等人类癌症的有效治疗靶点。迄今为止，三种蛋白酶体抑制剂，即硼替佐米（2003年）、卡非佐米（2012年）和伊沙佐米（2015年）已被美国食品药品监督管理局（FDA）批准用于治疗复发和/或难治性MM患者。本综述主要关注卡非佐米的生化特性、作用机制、毒性概况以及关键临床试验，卡非佐米是一种第二代蛋白酶体抑制剂，与蛋白酶体不可逆结合，以克服与硼替佐米相关的主要毒性和耐药性。
