Targeting the ubiquitin-proteasome pathway has emerged as a rational approach in 
the treatment of human cancer. Based on positive preclinical and clinical 
studies, bortezomib was subsequently approved for the clinical use as a 
front-line treatment for newly diagnosed multiple myeloma patients and for the 
treatment of relapsed/refractory multiple myeloma and mantle cell lymphoma, for 
which this drug has become the staple of treatment. The approval of bortezomib 
by the US Food and Drug Administration (FDA) represented a significant milestone 
as the first proteasome inhibitor to be implemented in the treatment of 
malignant disease. Bortezomib has shown a positive clinical benefit either alone 
or as a part of combination therapy to induce chemo-/radio-sensitization or 
overcome drug resistance. One of the major mechanisms of bortezomib associated 
with its anticancer activity is through upregulation of NOXA, which is a 
proapoptotic protein, and NOXA may interact with the anti-apoptotic proteins of 
Bcl-2 subfamily Bcl-X(L) and Bcl-2, and result in apoptotic cell death in 
malignant cells. Another important mechanism of bortezomib is through 
suppression of the NF-κB signaling pathway resulting in the down-regulation of 
its anti-apoptotic target genes. Although the majority of success achieved with 
bortezomib has been in hematological malignancies, its effect toward solid 
tumors has been less than encouraging. Additionally, the widespread clinical use 
of bortezomib continues to be hampered by the appearance of dose-limiting 
toxicities, drug-resistance and interference by some natural compounds. These 
findings could help guide physicians in refining the clinical use of bortezomib, 
and encourage basic scientists to generate next generation proteasome inhibitors 
that broaden the spectrum of efficacy and produce a more durable clinical 
response in cancer patients. Other desirable applications for the use of 
proteasome inhibitors include the development of inhibitors against specific E3 
ligases, which act at an early step in the ubiquitin-proteasome pathway, and the 
discovery of less toxic and novel proteasome inhibitors from natural products 
and traditional medicines, which may provide more viable drug candidates for 
cancer chemoprevention and the treatment of cancer patients in the future.