Augello Giuseppa, Azzolina Antonina, Rossi Filomena, Prencipe Filippo, Mangiatordi Giuseppe Felice, Saviano Michele, Ronga Luisa, Cervello Melchiorre, Tesauro Diego
Institute for Biomedical Research and Innovation (IRIB), CNR, Via Ugo LaMalfa 153, 90146 Palermo, Italy.
Department of Pharmacy and Interuniversity Research Centre on Bioactive Peptides (CIRPeB), University of Naples "Federico II", Via Montesano 49, 80131 Naples, Italy.
Pharmaceutics. 2023 Jan 31;15(2):466. doi: 10.3390/pharmaceutics15020466.
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. 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.
在非铂类抗肿瘤药物中，金配合物因其强大的抗增殖作用而受到越来越多的关注，其抗增殖作用通常通过非顺铂样作用机制实现。多项研究表明，许多细胞毒性金化合物，如N-杂环卡宾（NHC）-金（I）配合物，是有效的硫氧还蛋白还原酶（TrxR）抑制剂。人们认为，金与蛋白质靶点的配位作用还会改变许多其他途径。在此框架内，我们选择了两种基于芳香配体的金（I）配合物，用于在癌细胞上进行测试。与双[1,3-二乙基-4,5-双（4-甲氧基苯基）咪唑-2-亚基]金（I）溴化物（Au4BC）不同，双[1-甲基-3-吖啶咪唑啉-2-亚基]金（I）四氟硼酸盐（Au3BC）在体外抑制TrxR1活性。用Au4BC处理Huh7肝癌（HCC）细胞和MDA-MB-231三阴性乳腺癌（TNBC）细胞，可抑制细胞活力，提高活性氧（ROS）水平，导致DNA损伤，并诱导自噬和凋亡。值得注意的是，我们发现，尽管Au3BC抑制TrxR1活性，但未观察到对HCC和BC细胞活力的影响。在分子水平上，Au3BC通过诱导RAD51和p62蛋白表达上调，在Huh7和MDA-MB-231细胞中诱导了一种保护反应机制，这两种蛋白分别参与DNA损伤修复和自噬。在HCC细胞中进行基因敲低，通过显著降低细胞活力、诱导DNA损伤以及诱导凋亡和自噬，增加了细胞对Au3BC的敏感性。综上所述，这些结果表明，所测试的NHC-金配合物Au3BC和Au4BC表现出不同的作用机制，要么依赖于TrxR1抑制，要么与之无关。因此，Au3BC和Au4BC被认为是治疗HCC和BC的有前景的抗癌药物候选物。
