A dinuclear cyclometalated gold(iii)–phosphine complex targeting thioredoxin reductase inhibits hepatocellular carcinoma in vivo

Abstract

A stable gold(III)-phosphine complex [(C^N^C) 2 Au 2 (m-dppp)](CF 3 SO 3 ) 2 [Au3, HC^N^CH ¼ 2,6diphenylpyridine; dppp ¼ bis(diphenylphosphino)propane] displays potent in vitro cytotoxicity towards various cancers with sub-micromolar range cytotoxic IC 50 values, and is significantly more potent than its structural and iso-electronic platinum(II) analog [(C^N^N) 2 Pt 2 (m-dppp)](CF 3 SO 3 ) 2 (HC^N^N ¼ 6-phenyl-2,2 0 -bipyridine) and gold(III)-carbene complexes. Complex Au3 displays promising inhibition on tumor growth in animal models, and its acute and sub-chronic toxicities have been examined in mice and beagle dogs. Transcriptomic and connectivity map analyses have revealed that the transcriptional profile of Au3 is similar to those of inhibitors of thioredoxin reductase (TrxR) and inducers of endoplasmic reticulum (ER) stress. As we found that Au3 is also a nanomolar inhibitor of TrxR, a model of ER stress-induced cell death mediated by inhibition of TrxR is proposed. The transcriptomic analysis also leads to the identification of TRAIL, a ligand for death receptor 5 (DR5), as a synergistic agent of the anti-tumor activity of Au3. Collectively, our results demonstrate that the gold(III) complex Au3 effectively inhibits tumor growth in vivo, and displays promising cytotoxicity towards cancer cells in association with the inhibition of TrxR, induction of ER stress and also a death-receptor-dependent apoptotic pathway.

Cytotoxicity of Pyrazine-Based Cyclometalated (C^Npz^C)Au(III) Carbene Complexes: Impact of the Nature of the Ancillary Ligand on the Biological Properties

“…15,16 Compared with related Au(I) NHC complexes, the Au(III) complex 2 turned out to be more than twice as toxic as (benzimidazolylidene)AuCl against A549 cells 25b and more than 10 times more toxic against MCF-7 cells. 44 Moreover, the toxicities of complex 2 against A549 and MCF-7 cells compare well with those of [(benzimidazolylidene) 2 Au] + .…”

Design, synthesis and characterisation of new chimeric ruthenium(ii)–gold(i) complexes as improved cytotoxic agents

“…Indeed, a number of cytotoxic gold compounds were found to overcome cisplatin resistance in specific cancer cells 9–11 which makes them attractive potential therapeutics. In general, gold compounds manifest a high degree of cell toxicity; yet, the precise mechanisms of antitumor activity of gold compounds are not understood.…”

Enhanced anti-cancer activities of a gold(III) pyrrolidinedithiocarbamato complex incorporated in a biodegradable metal-organic framework

“…In the past decades, the in vitro and/or in vivo anti-cancer activities of some gold(III) complexes including that of porphyrins [31][32][33][34][35], carbene [50], terpyridine [51], diphenylpyridine [34], dinuclear oxo-bridged gold(III) complexes [52] and a series of gold(III) dithiocarbamato complexes [25] have been subsequently uncovered.…”

“…Apart from using strong sigma-donor ligands [31][32][33][34][35], another feasible approach to stabilize the highly oxidizing gold(III) metal center is the utilization of drug carriers or encapsulating materials. To facilitate the transport of anti-cancer active gold(III) complexes in biologically-relevant systems, some recent studies have demonstrated the use of gelatin-acacia [36], polyethylene glycol [37,38],…”