The ubiquitin-proteasome pathway regulates many basic cellular processes and has 
been proven to be a promising target for cancer therapy. Bortezomib is the first 
U.S. Food and Drug Administration (FDA) approved proteasome inhibitor used in 
the treatment of newly diagnosed multiple myeloma, relapsed/refractory multiple 
myeloma, and mantle cell lymphoma. The anti-cancer mechanisms of bortezomib 
elucidated by preclinical studies include: upregulation of proapoptotic proteins 
(e.g., Noxa, IκB), inhibition of NFκB and its anti-apoptotic target genes, 
suppression of several anti-apoptotic proteins (e.g., Bcl-XL, Bcl-2, and 
STAT-3), down-regulation of expression of several proteins involved in DNA 
repair pathways, and induction of endoplasmic reticulum (ER) stress and 
pro-apoptotic Unfolded Protein Response (UPR). Bortezomib has potent 
chemo-/radio-sensitizing effects and can overcome traditional drug resistance in 
tumors when used in combination with potential chemotherapies. Although 
bortezomib has been successful in improving clinical outcomes when used in 
hematological malignancies, relapse may occur in those patients who responded 
initially. Furthermore, some cytotoxicities (such as peripheral neuropathy) were 
found to be associated with bortezomib treatment. These observations have 
encouraged researchers to search for the next generation proteasome inhibitors 
(including carfilzomib and marizomib) that could overcome bortezomib resistance 
and have improved properties, reduced toxicities, and broader anticancer 
activities, based on the lessons learned from the mechanisms and use of 
bortezomib. This review summarizes the current status of bortezomib as well as 
several other proteasome inhibitors that are currently under clinical and 
preclinical investigation.