Proteasome Inhibitors and Lessons Learned from Their Mechanisms of Action and Resistance in Human Cancer

摘要: Selective protein degradation by the ubiquitin–proteasome pathway (UPP) is critical to cellular homeostasis, and dysregulation of UPP has been associated with human diseases including cancer. Proteasome inhibition as a strategy for cancer treatment was validated US Food Drug Administration approval proteasome inhibitor bortezomib multiple myeloma in 2003. After 10 years success, its combinational therapies have become staple treating relapsed/refractory myeloma. Unfortunately, several limitations, including, most notably, emergence resistance. To overcome resistance, approaches taken, development novel second-generation inhibitors, application rationalized bortezomib-based therapies, targeting sites outside proteasomal core well factors involved resistance mechanisms. Further understanding mechanisms inhibitors cancers will significantly improve current patient care.