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).
Highlights
Ovarian cancer is the 7th most common cancer in women worldwide with an estimated incidence rate of 6.1 per 100,000 [1]
The reported values show that the neutral complex Au(NHC) Cl (i.e. Au(NHC)) has a far greater lipophilicity than the cationic complex [Au(NHC)2]PF6(i.e. Au(NHC)2) in accord with expectations, since the positive charge of bis(carbene) species greatly increases its affinity for water
Upon comparing the effects of these two gold carbene complexes through all the experiments with those of control cells, it clearly emerged that Au(NHC)2 is a far more effective compound versus the three cancer cell lines used in this study
Summary
Ovarian cancer is the 7th most common cancer in women worldwide with an estimated incidence rate of 6.1 per 100,000 [1]. It represents the 8th cause of death from cancer in women worldwide [1]. Such dismal prognosis is due to several factors, including that most of ovarian cancer cases are diagnosed with advanced disease [2]. In addition to other cytotoxic drugs, several targeted agents such as PARP inhibitors (e.g. olaparib, rucaparib) or the anti VEGF MoAb bevacizumab may be used in ovarian cancer patients whose disease recurred [3]. Despite the availability of such new treatment options, five-year overall survival of all stage ovarian cancer is below 50% [1, 4]
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