The proteasome is a multicatalytic proteinase complex responsible for the 
degradation of most intracellular proteins, including proteins crucial to cell 
cycle regulation and programmed cell death, or apoptosis. In preclinical cancer 
models, proteasome inhibitors induce apoptosis, have in vivo antitumor efficacy, 
and sensitize malignant cells and tumors to the proapoptotic effects of 
conventional chemotherapeutics and radiation therapy. Interestingly, transformed 
cells display greater susceptibility to proteasome inhibition than nonmalignant 
cells. Therefore, proteasome inhibition holds promise as a novel approach to the 
treatment of cancer. Inhibitors of the proteasome impact on cells in part 
through down-regulation of nuclear factor kappaB, but also through modulation of 
cell cycle proteins and other pro- and antiapoptotic pathways. Bortezomib 
(VELCADE; formerly PS-341), the first such inhibitor to undergo clinical 
testing, has demonstrated impressive antitumor activity and manageable 
toxicities in Phase I and II trials both as a single agent, and in combination 
with other drugs. It has been approved recently by the Food and Drug 
Administration for therapy of patients with multiple myeloma who have received 
at least two prior regimens and progressed on the last of these. Ongoing 
preclinical evaluations of the mechanisms that underlie the antitumor effects of 
proteasome inhibitors, and clinical trials in a variety of tumor types, will 
allow additional refinement of the role these agents will play in cancer 
therapy. Below we discuss the rationale behind targeting the proteasome for 
cancer therapy, and review the preclinical and clinical data on proteasome 
inhibitors alone, and in combination with conventional chemotherapeutics.