Clinical development of novel proteasome inhibitors for cancer treatment

Abstract

Background: Emerging evidence demonstrates that targeting the tumor proteasome is a promising strategy for cancer therapy.

Objective: This review summarizes recent results from cancer clinical trials using specific proteasome inhibitors or some natural compounds that have proteasome-inhibitory effects.

Methods: A literature search was carried out using PubMed. Results about the clinical application of specific proteasome inhibitors and natural products with proteasome-inhibitory activity for cancer prevention or therapy were reviewed.

Results/conclusion: Bortezomib, the reversible proteasome inhibitor that first entered clinical trials, has been studied extensively as a single agent and in combination with glucocorticoids, cytotoxic agents, immunomodulatory drugs and radiation as treatment for multiple myeloma and other hematological malignancies. The results in some cases have been impressive. There is less evidence of bortezomib's efficacy in solid tumors. Novel irreversible proteasome inhibitors, NPI-0052 and carfilzomib, have also been developed and clinical trials are underway. Natural products with proteasome-inhibitory effects, such as green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG), soy isoflavone genistein, and the spice turmeric compound curcumin, have been studied alone and in combination with traditional chemotherapy and radiotherapy against various cancers. There is also interest in developing these natural compounds as potential chemopreventive agents.

Figures

Figure 1. The ubiquitin-proteasome pathway

Prior to proteasome degradation, target proteins are flagged with polyubiquitin chain transferred by ubiquitination system through interaction of the ubiquitin-activating enzyme E1, the ubiquitin-conjugating enzyme E2, and the ubiquitin ligase E3. Target proteins with polyubiquitin tag could be recognized by the 19S regulatory complex of the proteasome and fed into the 20S catalytic core, which has four stacked rings in αββα order. Each of the inner β rings contains seven β subunits with catalytic site facing the central cavity. Each of the outer α rings contains seven α subunits that serve as a gate for protein entry into the inner catalytic site.

Figure 2. Proteasome inhibition by several compounds used in clinical trials

β subunits of the proteasome have three catalytic sites: β1 (associated with caspase-like activity), β2 (associated with trypsin-like activity), and β5 (associated with chymotrypsin-like activity). Compounds in clinical trials could preferentially inhibit β5 chymotryptic site of the proteasome.

Figure 3

Chemical structures of proteasome inhibitors and some natural products with proteasome-inhibitory effects.