Toward understanding induction of oxidative stress and apoptosis by proteasome inhibitors.

Significance: Proteasome inhibitors (PIs) are used in the clinic for the treatment of hematopoietic malignancies. PI inhibitors induce endoplasmatic reticulum (ER) stress and oxidative stress, disruption of signaling pathways, mitochondrial dysfunction, and, eventually, cell death by apoptosis. PIs designated as clinical candidates include natural product derivatives and compounds developed by rational design and feature a wide diversity of structural elements. The vast amount of literature on this topic underscores PIs significance in driving basic research alongside therapeutic benefit.

Recent Advances: Research in recent years has brought an in-depth insight into the molecular mechanisms of PI-induced apoptosis. However, there are some paradoxes and controversies in the literature. In this review, the advances and uncertainties, in particular on the time course events that make cells commit to apoptosis, are discussed. In addition, some mechanisms of evolved PI resistance are presented, and speculations on the difference in sensitivity between cell or tumor types are brought forward. The review concludes by giving an outlook of recent methods that may be employed to describe the system biology of how PIs impact cell survival decisions.

Critical Issues: The biology of ER stress, reactive oxygen species (ROS) production, and apoptosis as induced by PIs is not well understood. Absorbed by the strong focus on PIs, one might overlook the importance of proteasome activity activators or modulators and the study of enzymatic pathways that lie up- or downstream from the proteasome function.

Future Directions: An increased understanding of the systems biology at mRNA and protein levels and the kinetics behind the interaction between PIs and cells is imperative. The design and synthesis of subunit specific inhibitors for each of the seven known proteasome activities and for the enzymes associated to proteasomes will aid in unraveling biology of the ubiquitin-proteasome system in relation to ER stress, ROS production, and apoptosis and will generate leads for therapeutic intervention.