Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing

Abstract

In the past 15 years, the proteasome has been validated as an anti-cancer drug target and 20S proteasome inhibitors (such as bortezomib and carfilzomib) have been approved by the FDA for the treatment of multiple myeloma and some other liquid tumors. However, there are shortcomings of clinical proteasome inhibitors, including severe toxicity, drug resistance, and no effect in solid tumors. At the same time, extensive research has been conducted in the areas of natural compounds and old drug repositioning towards the goal of discovering effective, economical, low toxicity proteasome-inhibitory anti-cancer drugs. A variety of dietary polyphenols, medicinal molecules, metallic complexes, and metal-binding compounds have been found to be able to selectively inhibit tumor cellular proteasomes and induce apoptotic cell death in vitro and in vivo, supporting the clinical success of specific 20S proteasome inhibitors bortezomib and carfilzomib. Therefore, the discovery of natural proteasome inhibitors and researching old drugs with proteasome-inhibitory properties may provide an alternative strategy for improving the current status of cancer treatment and even prevention.

Keywords: 26S proteasome; Cancer therapy and prevention; Drug repurposing; Metal complexes; Natural compounds; Proteasome inhibitor; Protein degradation; Tea polyphenols.

Fig. 1

The ubiquitin-proteasome system (UPS). The pathway begins with the conjugation of ubiquitin molecules to a substrate protein, forming a polyubiquitin chain through E1, E2 and E3 enzymes. The chain is then recognized and removed by the 19S lid of the 26S proteasome, followed by either release or degradation of the protein by the 20S catalytic core.

Fig. 2

The 26S proteasome and chemical structures of BTZ and CFZ. A. 26S proteasome: the 19S–associated DUBs (Rpn11, USP14, and UCHL5) are pictured, as are the alpha and beta subunits which make up 20S core particle; B. Bortezomib; C. carfilzomib

Fig. 3

Chemical structures of dietary flavonoids (a–f) and medicinal compounds (g–m). a. EGCG, b. genestein, c. myricetin, d. kaempferol, e. apigenin, f. quercetin, g. celastrol, h. pristimerin, i. triptolide, j. shikonin, k. withaferin A, l. curcumin, m. gambogic acid.

Fig. 4

Chemical structures of selected metal binding compounds. a. 8-hydroxyquinoline, b. clioquinol, c. pyrrolidine dithiocarbamate, d. disulfiram, e. sodium diethyldithiocarbamate.