Proteasome inhibition as a novel therapy in treating rheumatoid arthritis.
Rheumatoid arthritis (RA) is an erosive joint disease affecting about 1% of the population. The joint destruction is primarily mediated by special cells called fibroblast-like synoviocytes (FLS), which undergo an expansion forming a pannus that destroys the joint. Apoptosis has been rarely detected in the synovial lining. This has lead to the identification of pro-survival factors that are expressed in FLS at the sites of the pannus including mutant p53, hrd1, sentrin, and NF-kappaB. Current anti-inflammatory modalities only bring upon temporary relief and do not treat the pannus. Therefore, the FLS remain intact, joint destruction proceeds, patients relapse and eventually become resistant to all forms of therapy. To date, surgical removal of the pannus remains the only option to help delay further joint destruction. Therefore, we believe the future should hold a less invasive approach using a class of novel drugs called proteasome inhibitors to attenuate the growth of the FLS. We suggest the use of a novel proteasome inhibitor PS-341 to treat RA patients. PS-341 has been shown to induce apoptosis in many cancer cell lines and has lead to successful outcomes in phase II and III clinical trials of multiple myeloma. Moreover, PS-341 has been shown to sensitize a variety of cell lines to chemotherapeutic drugs, some of which are used as conventional therapy in RA. We hypothesize that PS-341 alone and/or in combination with conventional RA therapies could induce apoptosis in FLS in vitro and in vivo thereby treating the pannus. Prior to clinical use extensive research examining the effects of PS-341 in animal models of arthritis would be essential in order to understand the effects proteasome inhibition in disease biology. Overall, the purpose of our hypothesis is to suggest a realistic and alternative treatment for patients with refractory and non-refractory arthritic disease.
Brun
Jan
J
Apoptosis Research Centre, Children's Hospital of Eastern Ontario, 401 Smyth Road, Room 3103, Ottawa, ON, Canada. jan@arc.cheo.ca
D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D011480:Protease Inhibitors / Q000627:therapeutic use*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000627:therapeutic use; D013583:Synovial Membrane / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
D018501:Antirheumatic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib