Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

Abstract

The proteasome is the central component of the main cellular protein degradation pathway. During the past four decades, the critical function of the proteasome in numerous physiological processes has been revealed, and proteasome activity has been linked to various human diseases. The proteasome prevents the accumulation of misfolded proteins, controls the cell cycle, and regulates the immune response, to name a few important roles for this macromolecular “machine.” As a therapeutic target, proteasome inhibitors have been approved for the treatment of multiple myeloma and mantle cell lymphoma. However, inability to sufficiently inhibit proteasome activity at tolerated doses has hampered efforts to expand the scope of proteasome inhibitor-based therapies. With emerging new modalities in myeloma, it might seem challenging to develop additional proteasome-based therapies. However, the constant development of new applications for proteasome inhibitors and deeper insights into the intricacies of protein homeostasis suggest that proteasome inhibitors might have novel therapeutic applications. Herein, we summarize the latest advances in proteasome inhibitor development and discuss the future of proteasome inhibitors and other proteasome-based therapies in combating human diseases.

ER-Resident Transcription Factor Nrf1 Regulates Proteasome Expression and Beyond

“…Combating these resistance mechanisms can serve as a potentially useful strategy for making proteasome inhibitors more effective for treating cancers and solid tumors. However, there have been multiple observed mechanisms of resistance to proteasome inhibitors, such as mutations in PSMB5 (a target subunit of the proteasome inhibitor bortezomib), aberrant expression of UPS pathway components, and induction of drug efflux from cells [162]. The bounce-back response mediated by Nrf1 activation is one of the causes of resistance to proteasome inhibitors.…”

Non-Hematologic Toxicity of Bortezomib in Multiple Myeloma: The Neuromuscular and Cardiovascular Adverse Effects

“…Proteasome inhibitors (PIs) have been proved to be effective in MM patients and include the first-in-class PI bortezomib, the second-generation inhibitor carfilzomib, and ixazomib, the first oral PI [10]. These drugs target the 26S proteasome, a multi-subunit ATP-dependent enzymatic complex of the ubiquitin-proteasome system (UPS), the major protein degradation pathway in eukaryotic cells [10].…”

“…Proteasome inhibitors (PIs) have been proved to be effective in MM patients and include the first-in-class PI bortezomib, the second-generation inhibitor carfilzomib, and ixazomib, the first oral PI [10]. These drugs target the 26S proteasome, a multi-subunit ATP-dependent enzymatic complex of the ubiquitin-proteasome system (UPS), the major protein degradation pathway in eukaryotic cells [10]. The proteasome is made up of a barrel-shaped core particle consisting of four stacked heptameric rings, referred to as the 20S proteasome, and two 19S regulatory particles at the extremities [10].…”

“…These drugs target the 26S proteasome, a multi-subunit ATP-dependent enzymatic complex of the ubiquitin-proteasome system (UPS), the major protein degradation pathway in eukaryotic cells [10]. The proteasome is made up of a barrel-shaped core particle consisting of four stacked heptameric rings, referred to as the 20S proteasome, and two 19S regulatory particles at the extremities [10]. Proteasome substrates include misfolded, damaged, or mutant proteins and short-lived regulatory proteins that need to be removed for proper cellular function [10].…”

“…The proteasome is made up of a barrel-shaped core particle consisting of four stacked heptameric rings, referred to as the 20S proteasome, and two 19S regulatory particles at the extremities [10]. Proteasome substrates include misfolded, damaged, or mutant proteins and short-lived regulatory proteins that need to be removed for proper cellular function [10]. The accumulation of aberrantly folded proteins in the endoplasmic reticulum (ER) lumen can affect ER homeostasis and lead to a condition referred to as ER stress [10].…”