New Insights into the Behavior of NHC-Gold Complexes in Cancer Cells

Abstract

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.

Next Generation Gold Drugs and Probes: Chemistry and Biomedical Applications

“…Given the essential role of redox homeostasis in physiological and pathophysiological conditions, modulating redox enzymes such as TrxR via the formation of stable and irreversible adducts has enormous consequences for several cellular processes and regulating intracellular reactive oxygen species (ROS). − In cells that overexpress TrxR, such as parasites, cancer cells, and memory T cells, inhibition of the redox enzyme resulting in oxidative stress and eventually apoptotic cell death is therapeutically beneficial.…”

Reaction Behavior of [1,3-Diethyl-4,5-diphenyl-1H-imidazol-2-ylidene] Containing Gold(I/III) Complexes against Ingredients of the Cell Culture Medium and the Meaning on the Potential Use for Cancer Eradication Therapy

“…1 H NMR (400 MHz, chloroform-d) δ 7.48−7.27 (m, 20H), 4.35 (q, J = 7.3 Hz, 8H), 1.45 (t, J = 7.2 Hz, 12H). 13 (11). Complex 11 was synthesized according to the procedure described for 10 with the difference of using iodine (10 mg) instead of bromine.…”

“…11,26,27 To separate 8 from unreacted educts, purification by column chromatography was necessary. 11,27 Oxidation of 8 with either dichloroiodobenzene (PhICl 2 ), bromine, or iodine yielded the (NHC)gold(III) derivatives 9− 11, respectively. 26,41 All compounds could be obtained in high purity as determined by HPLC (>97%, Figures S1−S7 As expected, a low-field shift dependent on the electronic density was observed in the (NHC)Au(I)-X series (5 (X = Cl: 169.21 ppm) < 6 (X = Br: 172.83 ppm) < 7 (X = I: 179.96 ppm)).…”

“…These interesting results induced us to monitor the transformation of (NHC)gold(I) complexes in the cell culture medium more detailed on the example of halido[1,3-diethyl-4,5-diphenyl-1H-imidazol-2-ylidene]gold(I) (chlorido (5), bromido (6), iodido (7)), bis [1,3-diethyl-4,5-diphenyl-1Himidazol-2-ylidene]gold(I) (8), and bis[1,3-diethyl-4,5-diphenyl-1H-imidazol-2-ylidene]dihalidogold(III) (chlorido (9), bromido (10), iodido (11)) complexes.…”

“…19 In a similar way, the [(NHC) 2 Au(I)] + complex 8 was prepared from the bromido(NHC)gold(I) complex 6 by reaction with an equimolar amount of 4 for several days. 11,26,27 To separate 8 from unreacted educts, purification by column chromatography was necessary. 11,27 Oxidation of 8 with either dichloroiodobenzene (PhICl 2 ), bromine, or iodine yielded the (NHC)gold(III) derivatives 9− 11, respectively.…”