Overview of proteasome inhibitor-based anti-cancer therapies: perspective on bortezomib and second generation proteasome inhibitors versus future generation inhibitors of ubiquitin-proteasome system

Abstract

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 BTZ based 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.

Fig. 1. The ubiquitin-proteasome system (UPS)

The UPS-mediated protein degradation is an ATP-dependent process, involving two distinct steps, ubiquitination and degradation. First, ubiquitin (Ub) is covalently linked to a target protein by a multi-enzymatic system consisting of Ub-activating (E1), Ub-conjugating (E2), and Ub-ligating (E3). E1 activates an Ub monomer and transfers it to E2. E3 facilitates E2 to transfer the Ub to a reactive lysine residue of the target protein. The polyubiquitinated protein is then recognized by the 19S regulatory complex of the 26S proteasome and fed into the 20S catalytic core for degradation into oligopeptides and the ubiquitin molecules recycled.

Fig 2. Proteasome structures

The 26S proteasomes is a multiple-subunit protease complex composed of the 20S catalytic core and two 19S regulatory particles (A). The 20S core proteasome contains four stacked rings in a αββα arrangement, each ring containing 7 subunits (1 to 7). The outer α subunits serve as a gate to regulate protein entry into the inner catalytic site, while the inner β subunits possess proteolytic chymotrypsin-like (β5), trypsin-like (β2), and the PGPH-like (β1) activities (B and insert). Upon cytokine (e.g., interferon-γ or TNFα) stimulation, expression of β1i, β2i, and β5i dramatically increases and immunoproteasome 20Si forms, which is capped on each end by 11S proteasomes (B, insert, and C).