Proteasome Inhibitors
Proteasome inhibitors have effective anti-tumor activity in cell culture, inducing apoptosis by disrupting the regulated degradation of pro-growth cell cycle proteins. This approach of selectively inducing apoptosis in tumor cells has proven effective in animal models and human trials. Bortezomib, a molecule developed by Millennium Pharmaceuticals and marketed as Velcade, is the first proteasome inhibitor to reach clinical use as a chemotherapy agent. Bortezomib is used in the treatment of multiple myeloma. Notably, multiple myeloma has been observed to result in increased proteasome levels in blood serum that decrease to normal levels in response to successful chemotherapy. Studies in animals have indicated that bortezomib may also have clinically significant effects in pancreatic cancer. Preclinical and early clinical studies have been started to examine bortezomib's effectiveness in treating other B-cell-related cancers, particularly some types of non-Hodgkin's lymphoma.
The molecule ritonavir, marketed as Norvir, was developed as a protease inhibitor and used to target HIV infection. However, it has been shown to inhibit proteasomes as well as free proteases; to be specific, the chymotrypsin-like activity of the proteasome is inhibited by ritonavir, while the trypsin-like activity is somewhat enhanced. Studies in animal models suggest that ritonavir may have inhibitory effects on the growth of glioma cells.
Proteasome inhibitors have also shown promise in treating autoimmune diseases in animal models. For example, studies in mice bearing human skin grafts found a reduction in the size of lesions from psoriasis after treatment with a proteasome inhibitor. Inhibitors also show positive effects in rodent models of asthma.
Labeling and inhibition of the proteasome is also of interest in laboratory settings for both in vitro and in vivo study of proteasomal activity in cells. The most commonly used laboratory inhibitors are lactacystin, a natural product synthesized by Streptomyces bacteria, and peptide MG132. Fluorescent inhibitors have also been developed to specifically label the active sites of the assembled proteasome.
Read more about this topic: Proteasome