Proteasome inhibitors: poisons and remedies.

The proteasome inhibitor bortezomib has been approved as a cytostatic drug for the therapy of multiple myeloma, and is currently being tested in clinical trials for a variety of other malignancies. At the same time, a growing number of animal studies suggest that proteasome inhibitors may also prove to be valuable remedies for the treatment of non-tumorous diseases. In this review, we will revisit the current applications of proteasome inhibitors in clinical research according to the cellular effects of proteasome inhibitors as poisons, which induce apoptosis, or as remedies, which modulate cellular function and protect from cell death. We postulate that the correct distinction of a poison from a remedy depends on cell type and on the degree of proteasome inhibition. Dose-dependent and differential inhibition of the proteasome may affect specific sets of substrates, thereby conferring substrate specificity. According to this idea, we suggest that inhibition of the proteasome to a defined degree may offer a promising tool in achieving desired therapeutic effects in various diseases. (c) 2007 Wiley Periodicals, Inc.