Overview of Proteasome Inhibitor-Based Anti-cancer Therapies: Perspective on Bortezomib and Second Generation Proteasome Inhibitors versus Future Generation Inhibitors of Ubiquitin-Proteasome System
Q. Ping Dou and Jeffrey A. Zonder
Affiliation: Barbara Ann Karmanos Cancer Institute and Department of Oncology, Wayne State University School of Medicine, 540.1 HWCRC, 4100 John R Road, Detroit, MI 48201.
Keywords: Bortezomib, carfilzomib, combination therapy, immunoproteasomes, multiple myeloma, proteasome inhibitor,
resistance to proteasome inhibitors, ubiquitin-proteasome pathway.
Over the past ten years, proteasome inhibition has emerged as an effective therapeutic strategy for treating
multiple myeloma (MM) and some lymphomas. In 2003, Bortezomib (BTZ) became the first proteasome inhibitor
approved by the U.S. Food and Drug Administration (FDA). BTZ-based therapies have become a staple for the treatment
of MM at all stages of the disease. The survival rate of MM patients has improved significantly since clinical introduction
of BTZ and other immunomodulatory drugs. However, BTZ has several limitations. Not all patients respond to BTZbased
therapies and relapse occurs in many patients who initially responded. Solid tumors, in particular, are often resistant
to BTZ. Furthermore, BTZ can induce dose-limiting peripheral neuropathy (PN). The second generation proteasome inhibitor
Carfizomib (CFZ; U.S. FDA approved in August 2012) induces responses in a minority of MM patients relapsed from or
refractory to BTZ. There is less PN compared to BTZ. Four other second-generation proteasome inhibitors (Ixazomib,
Delanzomib, Oprozomib and Marizomib) with different pharmacologic properties and broader anticancer activities, have
also shown some clinical activity in bortezomib-resistant cancers. While the mechanism of resistance to bortezomib in
human cancers still remains to be fully understood, targeting the immunoproteasome, ubiquitin E3 ligases, the 19S
proteasome and deubiquitinases in pre-clinical studies represents possible directions for future generation inhibitors of
ubiquitin-proteasome system in the treatment of MM and other cancers.
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