Mechanism of action of bortezomib in multiple myeloma therapy

Abstract

A proteasome inhibitor, bortezomib (BTZ), was initially reported as an inhibitor of the NF-κB pathway, which plays a critical role in the pathogenesis of multiple myeloma (MM). The NF-κB activity of MM cells is mediated via two distinguishable pathways, canonical and non-canonical, which showed opposing action after BTZ treatment in MM cells. Recent studies of proteasome inhibition in MM cells reveal that accumulation of unfolded proteins in the endoplasmic reticulum (ER), so called ER stress, triggered several pro-apoptotic factors and cell stress such as Reactive Oxygen Species (ROS) accumulation, which is considered to be the main mechanism of action of BTZ-induced apoptosis. Several factors associated with ER stress and unfolded protein response (UPR), have been identified with sensitivity of BTZ treatment. Low levels of XBP1, ATF3, and ATF4, which regulate UPR and ER stress-induced apoptosis, have been observed in poor responders to BTZ treatment, and three other genes, KLF9, Nampt, and CDK5, are associated with response to BTZ-containing therapy. These findings contribute to a better understanding of the mechanism of BTZ-induced apoptosis in MM cells, and further study is needed to develop potential predictive biomarkers of efficacy of BTZ-containing therapy.