| Autor: |
Augello G; Institute for Biomedical Research and Innovation (IRIB), CNR, Via Ugo LaMalfa 153, 90146 Palermo, Italy., Azzolina A; Institute for Biomedical Research and Innovation (IRIB), CNR, Via Ugo LaMalfa 153, 90146 Palermo, Italy., Rossi F; Department of Pharmacy and Interuniversity Research Centre on Bioactive Peptides (CIRPeB), University of Naples 'Federico II', Via Montesano 49, 80131 Naples, Italy., Prencipe F; Institute of Crystallography (IC), CNR, Via Amendola 122/O, 70126 Bari, Italy., Mangiatordi GF; Institute of Crystallography (IC), CNR, Via Amendola 122/O, 70126 Bari, Italy., Saviano M; Institute of Crystallography (IC), CNR, URT Caserta, Via Vivaldi 43, 81100 Caserta, Italy., Ronga L; Institut des Sciences Analytiques et de Physico-Chimie Pour l'Environnement et les Matériaux, Université de Pau et des Pays de l'Adour, E2S UPPA, CNRS, IPREM, 64053 Pau, France., Cervello M; Institute for Biomedical Research and Innovation (IRIB), CNR, Via Ugo LaMalfa 153, 90146 Palermo, Italy., Tesauro D; Department of Pharmacy and Interuniversity Research Centre on Bioactive Peptides (CIRPeB), University of Naples 'Federico II', Via Montesano 49, 80131 Naples, Italy. |
| Abstrakt: |
Among the non-platinum antitumor agents, gold complexes have received increased attention owing to their strong antiproliferative effects, which generally occur through non-cisplatin-like mechanisms of action. Several studies have revealed that many cytotoxic gold compounds, such as N-heterocyclic carbene (NHC)-gold(I) complexes, are potent thioredoxin reductase (TrxR) inhibitors. Many other pathways have been supposed to be altered by gold coordination to protein targets. Within this frame, we have selected two gold(I) complexes based on aromatic ligands to be tested on cancer cells. Differently from bis [1,3-diethyl-4,5-bis(4-methoxyphenyl)imidazol-2-ylidene]gold(I) bromide (Au4BC), bis [1-methyl-3-acridineimidazolin-2-ylidene]gold(I) tetrafluoroborate (Au3BC) inhibited TrxR1 activity in vitro. Treatment of Huh7 hepatocellular carcinoma (HCC) cells, and MDA-MB-231 triple-negative breast cancer (TNBC) cells, with Au4BC inhibited cell viability, increased reactive oxygen species (ROS) levels, caused DNA damage, and induced autophagy and apoptosis. Notably, we found that, although Au3BC inhibited TrxR1 activity, no effect on the cell viabilities of HCC and BC cells was observed. At the molecular level, Au3BC induced a protective response mechanism in Huh7 and MDA-MB-231 cells, by inducing up-regulation of RAD51 and p62 protein expression, two proteins involved in DNA damage repair and autophagy, respectively. RAD51 gene knock-down in HCC cells increased cell sensitivity to Au3BC by significant reduction of cell viability, induction of DNA damage, and induction of apoptosis and autophagy. All together, these results suggest that the tested NHC-Gold complexes, Au3BC and Au4BC, showed different mechanisms of action, either dependent or independent of TrxR1 inhibition. As a result, Au3BC and Au4BC were found to be promising candidates as anticancer drugs for the treatment of HCC and BC. |
