Research Laboratories, Immunology Area, Children's Hospital Bambino Gesu, Rome, Italy.
Curr Drug Targets. 2012 Dec;13(13):1665-75. doi: 10.2174/138945012803530053.
Since the discovery of proteasome in the late 1980s, the ubiquitin-proteasome system has been found to exert an important physiological function in all the cells of living organisms - that of ensuring homeostasis. All cell cycle, apoptosis, differentiation, transcription, protein quality control and antigen processing activities require the efficiency of this system. As a matter of fact, several pathological conditions are characterized by deregulation of the ubiquitinproteasome system. These include cancer, neurodegenerative diseases, viral infections and autoimmune diseases. This has stimulated interest in developing proteasome inhibitors for their treatment, but clinical application has been limited due to the toxicity of these compounds. Following experiences with the first proteasome inhibitor, bortezomib, in the treatment of hematologic malignancies, several molecules with proteasome inhibitor properties were discovered and they were also exploited for the treatment of experimental models of human autoimmunity. Autoimmune disorders are a heterogeneous group of conditions, both organ- and non-organ-specific, whose incidence is increasing worldwide. This has stimulated interest in discovering novel predictive strategies and therapeutics. Here we provide a review of the use of proteasome inhibitors in treating autoimmune conditions and, in particular, systemic autoimmune diseases, inflammatory bowel disease, multiple sclerosis and organ-specific autoimmune diseases. We also present perspectives derived from more recently discovered compounds with proteasome inhibitor activity and discuss their potential in the management of these disorders.
自 20 世纪 80 年代末发现蛋白酶体以来，泛素-蛋白酶体系统在所有生物细胞中发挥着重要的生理功能——确保内稳态。所有的细胞周期、凋亡、分化、转录、蛋白质质量控制和抗原处理活动都需要这个系统的效率。事实上，几种病理状况的特点是泛素蛋白酶体系统的失调。这些包括癌症、神经退行性疾病、病毒感染和自身免疫性疾病。这激发了人们对开发蛋白酶体抑制剂的兴趣，用于治疗这些疾病，但由于这些化合物的毒性，临床应用受到限制。在硼替佐米作为治疗血液恶性肿瘤的第一种蛋白酶体抑制剂的经验之后，发现了几种具有蛋白酶体抑制剂特性的分子，并将其用于治疗人类自身免疫的实验模型。自身免疫性疾病是一组异质性疾病，包括器官特异性和非器官特异性疾病，其发病率在全球范围内呈上升趋势。这激发了人们对发现新的预测策略和治疗方法的兴趣。在这里，我们回顾了蛋白酶体抑制剂在治疗自身免疫性疾病，特别是系统性自身免疫性疾病、炎症性肠病、多发性硬化症和器官特异性自身免疫性疾病中的应用。我们还介绍了最近发现的具有蛋白酶体抑制剂活性的化合物的前景，并讨论了它们在这些疾病治疗中的潜在应用。
