Proteasome inhibition: a new anti-inflammatory strategy.
The ubiquitin-proteasome pathway has a central role in the selective degradation of intracellular proteins. Among the key proteins modulated by the proteasome are those involved in the control of inflammatory processes, cell cycle regulation, and gene expression. Consequently proteasome inhibition is a potential treatment option for cancer and inflammatory conditions. Thus far, proof of principle has been obtained from studies in numerous animal models for a variety of human diseases including cancer, reperfusion injury, and inflammatory conditions such as rheumatoid arthritis, asthma, multiple sclerosis, and psoriasis. Two proteasome inhibitors, each representing a unique chemical class, are currently under clinical evaluation. Velcade (PS-341) is currently being evaluated in multiple phase II clinical trials for several solid tumor indications and has just entered a phase III trial for multiple myeloma. PS-519, representing another class of inhibitors, focuses on the inflammatory events following ischemia and reperfusion injury. Since proteasome inhibitors exhibit anti-inflammatory and antiproliferative effects, diseases characterized by both of these processes simultaneously, as is the case in rheumatoid arthritis or psoriasis, might also represent clinical opportunities for such drugs.
Elliott
Peter J
PJ
CombinatoRx Inc., Boston, Massachusetts, USA.
Zollner
Thomas Matthias
TM
Boehncke
Wolf-Henning
WH
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001249:Asthma / Q000188:drug therapy; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D002986:Clinical Trials as Topic; D003546:Cysteine Endopeptidases; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D008239:Lysine / Q000737:chemistry; D008954:Models, Biological; D008956:Models, Chemical; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009103:Multiple Sclerosis / Q000188:drug therapy; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy; D010455:Peptides / Q000737:chemistry; D011480:Protease Inhibitors / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex; D011565:Psoriasis / Q000188:drug therapy; D011719:Pyrazines / Q000627:therapeutic use; D015427:Reperfusion Injury
D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D001897:Boronic Acids; D009097:Multienzyme Complexes; D016328:NF-kappa B; C411422:PS519; D010455:Peptides; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D008239:Lysine; D000111:Acetylcysteine