Antiproliferative effects of two gold(I)-N-heterocyclic carbene complexes in A2780 human ovarian cancer cells: a comparative proteomic study
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Francesca Magherini1, Tania Fiaschi1, Elisa Valocchia1, Matteo Becatti1, Alessandro Pratesi2, Tiziano Marzo2,3, Lara Massai2, Chiara Gabbiani3, Ida Landini4, Stefania Nobili5, Enrico Mini5, Luigi Messori2, Alessandra Modesti1 and Tania Gamberi1
1Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
2Department of Chemistry “Ugo Schiff”, University of Florence, Florence, Italy
3Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy
4Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
5Department of Health Sciences, University of Florence, Florence, Italy
Tania Gamberi, email: [email protected]
Luigi Messori, email: [email protected]
Keywords: gold(I)-N-heterocyclic carbene complexes; A2780 human ovarian cancer cells; proteomics; mitochondrial metabolism; thioredoxin reductase
Received: August 13, 2017 Accepted: May 19, 2018 Published: June 15, 2018
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).
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