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Proteasome inhibition: a new anti-inflammatory strategy

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Abstract

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.

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Abbreviations

CLA :

Cutaneous lymphocyte-associated antigen

EAE :

Experimental autoimmune encephalomyelitis

IκB :

Nuclear factor κB inhibitor

IL :

Interleukin

NF-κB :

Nuclear factor κB

TNF :

Tumor necrosis factor

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Authors and Affiliations

  1. CombinatoRx Inc., Boston, Massachusetts, USA

    Peter J. Elliott

  2. RBA Dermatology, Schering AG, Berlin, Germany

    Thomas Matthias Zollner

  3. Department of Dermatology, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany

    Wolf-Henning Boehncke

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  1. Peter J. Elliott
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  2. Thomas Matthias Zollner
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  3. Wolf-Henning Boehncke
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Correspondence to Wolf-Henning Boehncke.

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Elliott, P.J., Zollner, T.M. & Boehncke, WH. Proteasome inhibition: a new anti-inflammatory strategy. J Mol Med 81, 235–245 (2003). https://doi.org/10.1007/s00109-003-0422-2

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