The proteasome inhibitor bortezomib in programmed cell death and cancer therapy

Abstract

The 26S proteasome is a ubiquitous enzyme complex which is responsible for degrading proteins that regulate essential cellular functions, such as cell-cycle control, cellular adhesion, proliferation, apoptosis and angiogenesis. The inhibition of proteasome dysregulates these signalling pathways, ultimately leading to cell cycle arrest and apoptosis in many cell types. Importantly, preclinical research has shown that cancer cells seem to be more sensitive to the proapoptotic effects of proteasome inhibition than normal cells. First-generation proteasome inhibitors lacked usefulness because of broad specificity and irreversible binding to the proteasome. However, the peptide boronic acid proteasome inhibitor bortezomib allowed for selective, reversible binding. Bortezomib (VELCADE; formerly PS-341) is the first proteasome inhibitor to enter clinical studies. It exhibited strong antitumor activity both in in vitro and in vivo laboratory studies against many solid and haematologic tumor types. Bortezomib specifically promoted apoptosis of tumor cells through a pleitropic mechanisms, including the inhibition of the nuclear factor kappa B (NF-B), accumulation of p53, changes in the levels of Bcl-2 family members with increase in the level of pro-apoptotic members and decrease in that of anti-apoptotic ones, activation of c-Jun/JNK/AP-1 pathway with consequent activation of the transcriptional targets such as c-Jun, FasL and Bim. Bortezomib has demonstrated 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 the treatment of advanced multiple myeloma (MM). This article focuses on the preclinical rationale for bortezomib’s application for cancer therapy and provides a review of the current status of bortezomib in tumor clinical trials.