Voorhees Peter M, Orlowski Robert Z
Department of Medicine, Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
Annu Rev Pharmacol Toxicol. 2006;46:189-213. doi: 10.1146/annurev.pharmtox.46.120604.141300.
The proteasome, a multicatalytic proteinase complex, is responsible for the majority of intracellular protein degradation. Pharmacologic inhibitors of the proteasome possess in vitro and in vivo antitumor activity, and bortezomib, the first such agent to undergo clinical testing, has significant efficacy against multiple myeloma and non-Hodgkin lymphoma (NHL). Preclinical studies demonstrate that proteasome inhibition potentiates the activity of other cancer therapeutics, in part by downregulating chemoresistance pathways. Early clinical studies of bortezomib-based combinations, showing encouraging activity, support this observation. Molecular characterization of resistance to proteasome inhibitors has revealed novel therapeutic targets for sensitizing malignancies to these agents, such as the heat shock pathway. Below, we review the pharmacologic, preclinical, and clinical data that have paved the way for the use of proteasome inhibitors for cancer therapy; outline strategies aimed at enhancing the efficacy of proteasome inhibitors; and review other potential targets in the ubiquitin proteasome pathway for the treatment of cancer.
蛋白酶体是一种多催化蛋白酶复合物，负责细胞内大部分蛋白质的降解。蛋白酶体的药理抑制剂具有体外和体内抗肿瘤活性，硼替佐米是首个进行临床试验的此类药物，对多发性骨髓瘤和非霍奇金淋巴瘤（NHL）有显著疗效。临床前研究表明，蛋白酶体抑制可增强其他癌症治疗药物的活性，部分原因是下调化疗耐药途径。基于硼替佐米的联合治疗的早期临床研究显示出令人鼓舞的活性，支持了这一观察结果。对蛋白酶体抑制剂耐药的分子特征分析揭示了使恶性肿瘤对这些药物敏感的新治疗靶点，如热休克途径。以下，我们回顾为蛋白酶体抑制剂用于癌症治疗铺平道路的药理、临床前和临床数据；概述旨在提高蛋白酶体抑制剂疗效的策略；并回顾泛素蛋白酶体途径中用于癌症治疗的其他潜在靶点。
