Cellular homeostasis requires routine degradation of key regulatory proteins, 
including tumor suppressor gene products, transcription factors, cell-cycle 
proteins and their inhibitors, as well as damaged and misfolded proteins. A 
critical part of this process is mediated by the 26S proteasome, a multi-subunit 
enzyme found in the nucleus and cytoplasm of all eukaryotic cells. Because of 
its essential role in many cellular processes controlling growth and survival, 
the proteasome has been identified as a potential target for cancer therapy. 
Drugs known to inhibit proteasome activity have been shown to induce cell-cycle 
arrest and programmed cell death (apoptosis). The impact of this finding is 
heightened by research showing that cancer cells are more sensitive to the 
proapoptotic effects of proteasome inhibition than normal cells. Preclinical 
evidence using bortezomib, the only proteasome inhibitor to enter clinical 
trials, suggests that proteasome inhibition may be effective in the treatment of 
hematologic and solid malignancies by promoting apoptosis, retarding 
angiogenesis, and inhibiting tumor cell adhesion and production of growth 
factors by acting on molecules such as nuclear factor-kappaB. Further 
preclinical evidence suggests that the antitumor effects of cytotoxic 
chemotherapy or radiotherapy may be enhanced by the addition of a proteasome 
inhibitor. Bortezomib was recently approved for the treatment of multiple 
myeloma. It is currently being investigated, both as a single agent and in 
combination, in phase I and II trials in a variety of tumor types.