The role of proteasome in malignant diseases.

Proteasomal degradation is the main mechanism accounting for intracellular protein degradation. Not only is the proteasome involved in physiological protein turnover, it is also called into play by processes such as signal transduction, cell cycle, and apoptosis. Despite the ubiquitous distribution of the proteasome and its putative essential function, proteasome inhibitors have been developed that can be safely administered with acceptable side effects. Importantly, these compounds have been found to possess antitumor activity and are presently incorporated into the treatment of multiple myeloma and mantle cell lymphoma. In 2003, bortezomib (velcade) was the first compound in this category to have received FDA approval. The mechanisms for the antitumor activity of bortezomib and related drugs remain elusive. NF- kappaB inhibition by proteasome inhibitors may play a role in some instances. Recently, terminally differentiated plasma cells have been shown to downregulate proteasome expression and overall proteasome activity, which may account for the exquisite susceptibility of multiple myeloma cells to proteasome inhibition. New proteasome inhibitors with improved pharmacological properties are being developed and will soon enter clinical experimentation. Finally, studies addressing the usefulness of these compounds in other types of malignancies are ongoing and may soon expand the number of applications of these new therapeutic agents.