Antiproliferative effects of two gold(I)-N-heterocyclic carbene complexes in A2780 human ovarian cancer cells: a comparative proteomic study

Abstract

Au(NHC) and Au(NHC)2, i.e. a monocarbene gold(I) complex and the corresponding bis(carbene) complex, are two structurally related compounds, endowed with cytotoxic properties against several cancer cell lines. Herein, we explore the molecular and cellular mechanisms at the basis of their cytotoxicity in A2780 human ovarian cancer cells. Through a comparative proteomic analysis, we demonstrated that the number of modulated proteins is far larger in Au(NHC)2-treated than in Au(NHC)-treated A2780 cells. Both gold compounds mainly affected proteins belonging to the following functional classes: protein synthesis, metabolism, cytoskeleton and stress response and chaperones. Particularly, Au(NHC)2 gave rise to an evident upregulation of several glycolytic enzymes. Moreover, only Au(NHC)2 triggered a net impairment of respiration and a metabolic shift towards glycolysis, suggesting that mitochondria are relevant cellular targets. We also found that both carbenes, similarly to the gold(I) compound auranofin, caused a strong inhibition of the seleno-enzyme thioredoxin reductase (TrxR). In conclusion, we highlighted that coordination of two carbene ligands to the same gold(I) center greatly enhances the antiproliferative effects of the resulting compound in comparison to the monocarbene derivative. Moreover, TrxR inhibition and metabolic impairment seem to play a major role in the Au(NHC)2 cytotoxicity. Overall, these antiproliferative effects were also confirmed on other two human ovarian cancer cell lines (i.e. SKOV3 and IGROV1).

Reactions of Medicinal Gold(III) Compounds With Proteins and Peptides Explored by Electrospray Ionization Mass Spectrometry and Complementary Biophysical Methods

“…This prompted investigators to analyze in detail the reactions of medicinal gold compounds with proteins. A systematic investigation on the interactions of the reference gold(I) drug auranofin with a series of model proteins, i.e., human serum albumin, carbonic anhydrase, superoxide dismutase, and hemoglobin, was recently carried out in our laboratory through mass spectrometry, and the resulting adducts could be characterized in molecular detail (Pratesi et al, 2016(Pratesi et al, , 2018(Pratesi et al, , 2019Magherini et al, 2018;Cirri et al, 2019;Zoppi et al, 2020). These studies revealed that auranofin targets quite selectively the free cysteine residues of proteins (Pratesi et al, 2018;Zoppi et al, 2020).…”

Cancer cell-selective modulation of mitochondrial respiration and metabolism by potent organogold(iii) dithiocarbamates

“…S84-S103 †). Whereas gold dithiocarbamates are known to react with thiols, 45,49,51,69 detailed studies to unravel the potential mechanism of activity do not exist. HPLC trace of the reaction solution revealed one distinct band at a different retention time (R t -5.00 minutes) from 2a (R t -6.03 minutes) or GSH (R t -1.72 minutes) ( Fig.…”

Nanomedicine and Onco-Immunotherapy: From the Bench to Bedside to Biomarkers

“…Gold-NP, polymer NP or liposomes are also used as carriers of tumour-peptide vaccines that play an important role in tumour immunotherapy [ 2 , 23 , 24 ]. Chemotherapy based on platinum (II), ruthenium and gold (III) compounds also kills tumour cells [ 25 , 26 ]. One of the most studied gold (III) compounds is the anti-rheumatic drug Auranofin as a cancer treatment [ 2 , 27 ].…”