Proteasome inhibitors: a new perspective for treating autoimmune diseases

Abstract

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.