Selected Cytotoxic Gold Compounds cause Significant Inhibition of 20S Proteasome Catalytic Activities

Six structurally diverse cytotoxic gold compounds are reported to cause profound and differential inhibition of
the three main catalytic activities of purified 20S proteasome whilst auranofin, an established gold(I) drug in
clinical use, is nearly ineffective. In particular, the gold(I) complex [(pbiH)Au(PPh3)]PF6, turns out to be the
most potent inhibitor of all three enzyme activities with sub-micromolar IC50 values. The present results further
support the viewthat proteasome inhibitionmay play amajor – yet not exclusive – role in the cytotoxic actions of
gold based anticancer agents.
© 2014 Elsevier Inc. All rights reserved.
The ubiquitin/proteasome system (UPS hereafter) is a complex
molecular machinery specifically devoted to the turnover of intracellular
proteins in eukaryotic cells; owing to the discovery of UPS and to the
assessment of its biological relevance, Hershko and Ciechanover were
awarded the 2004 Nobel Prize in Chemistry [1].
The proteasome most exclusively used in mammals is the cytosolic
26S proteasome, ~2 MDa in molecular mass; it contains one 20S core
particle capped by two 19S regulatory subunits (Fig. 1). The 20S core
is hollow and forms a cavity where ubiquitin-tagged proteins are degraded.
Each end of the core particle associates with a 19S regulatory
subunit containing multiple ATPase sites and ubiquitin binding sites;
this structure is capable of recognising poly-ubiquitinated proteins
that are then transferred to the catalytic interior [2]. Threemain enzyme
activities were identified in the proteasome, namely the chymotrypticlike
(CT-L), the caspase-like (C-L; also known as post glutamyl-peptide
hydrolyzing, PGPH)