Sri Ramachandra Medical College and Research Institute, Sri Ramachandra University, Chennai, India.
Int J Rheum Dis. 2012 Jun;15(3):249-60. doi: 10.1111/j.1756-185X.2012.01737.x. Epub 2012 May 9.
In eukaryotes the ubiquitin proteasome pathway plays an important role in cellular homeostasis and also it exerts a critical role in regulating a wide variety of cellular pathways, including cell growth and proliferation, apoptosis, DNA repair, transcription and immune response. Defects in these pathways have been implicated in a number of human pathologies. Inhibition of the ubiquitin proteasome pathway by proteasome inhibitors may be a rational therapeutic approach for various diseases, such as cancer and inflammatory diseases. Many of the critical cytokine and chemokine mediators of the progression of rheumatoid arthritis are regulated by nuclear factor kappa B (NF-κB). In peptidoglycan/polysaccharide-induced polyarthritis, proteasome inhibitors limit the overall inflammation, reduce NF-κB activation, decrease cellular adhesion molecule expression, inhibit nitric oxide synthase, attenuate circulating levels of proinflammatory cytokine interleukin-6 and reduce the arthritis index and swelling in the joints of the animals. Since proteasome inhibitors exhibit anti-inflammatory and anti proliferative effects, diseases characterized by both of these processes such as rheumatoid arthritis might also represent clinical opportunities for such drugs. The regulation of the proteasomal complex by proteasome inhibitors also has implications and potential benefits for the treatment of rheumatoid arthritis. This review summarizes the ubiquitin proteasome pathway, the structure of 26S proteasomes and types of proteasome inhibitors, with their actions, and clinical applications of proteasome inhibitors in various diseases.
在真核生物中，泛素蛋白酶体途径在细胞内稳态中起着重要作用，它在调节多种细胞途径中也起着关键作用，包括细胞生长和增殖、细胞凋亡、DNA 修复、转录和免疫反应。这些途径的缺陷与许多人类病理学有关。蛋白酶体抑制剂对泛素蛋白酶体途径的抑制可能是治疗各种疾病（如癌症和炎症性疾病）的合理方法。许多类风湿关节炎进展的关键细胞因子和趋化因子介质受核因子 kappa B（NF-κB）调节。在肽聚糖/多糖诱导的多关节炎中，蛋白酶体抑制剂限制了整体炎症，降低了 NF-κB 的激活，减少了细胞黏附分子的表达，抑制了一氧化氮合酶，降低了循环中促炎细胞因子白细胞介素-6 的水平，并减轻了动物关节的关节炎指数和肿胀。由于蛋白酶体抑制剂具有抗炎和抗增殖作用，因此具有这两种作用的疾病（如类风湿关节炎）也可能代表此类药物的临床机会。蛋白酶体抑制剂对蛋白酶体复合物的调节也对类风湿关节炎的治疗具有意义和潜在益处。这篇综述总结了泛素蛋白酶体途径、26S 蛋白酶体的结构和蛋白酶体抑制剂的类型，及其作用，以及蛋白酶体抑制剂在各种疾病中的临床应用。
