Department of Health Sciences, University of Florence, Florence, Italy.
Department of Chemistry "Ugo Schiff", University of Florence, Florence, Italy.
J Inorg Biochem. 2020 Jul;208:111079. doi: 10.1016/j.jinorgbio.2020.111079. Epub 2020 Mar 28.
The antiproliferative properties of a series of structurally-related gold(I) and silver(I) linear complexes inspired to the clinically established gold-based drug auranofin were investigated in A2780 ovarian cancer cells and in their auranofin (A2780/AF-R) and cisplatin (A2780/CDDP-R) resistant counterparts. In A2780 cells and in the cisplatin-resistant subline, gold-based analogues manifested a cytotoxicity profile comparable or superior to auranofin, while the silver-based analogues were less active; both gold and silver complexes overcame cisplatin resistance. Yet, a high degree of cross resistance toward gold analogues was noticed in A2780/AF-R cells. In the same cell line cross-resistance for silver analogues was also observed, though lower. All metal complexes were scrutinized for their ability to inhibit thioredoxin reductase (TrxR), the putative primary target for auranofin: overall, gold compounds were more potent TrxR inhibitors than the corresponding silver compounds, probably, as the consequence of the stronger binding of gold to the active site selenocysteine residue. These results highlight that the thiosugar ligand of auranofin is not essential for cytotoxicity while the nature of the metal center (gold/silver) plays a relevant role in its modulation. In addition, a rather clear correlation was found between cytotoxic potency of tested compounds and their ability to inhibit TrxR activity, being gold compounds more effective than silver analogues. However, the residual TrxR activity, measured in A2780 cells treated with the half-maximal inhibitory concentrations of various metal complexes, resulted far higher than expected. These results suggest that additional cytotoxic mechanisms must be operative. The implications of these results are discussed.
一系列结构相关的金（I）和银（I）线性配合物具有抗增殖特性，这些配合物的结构受到临床应用的金基药物金诺芬的启发，研究人员在 A2780 卵巢癌细胞及其金诺芬（A2780/AF-R）和顺铂（A2780/CDDP-R）耐药细胞中研究了这些配合物的特性。在 A2780 细胞和顺铂耐药亚系中，金基类似物表现出与金诺芬相当或更优的细胞毒性特征，而银基类似物则活性较低；金和银配合物均能克服顺铂耐药性。然而，在 A2780/AF-R 细胞中，对金类似物存在高度交叉耐药性。在同一细胞系中，也观察到对银类似物的交叉耐药性，但程度较低。研究人员还研究了所有金属配合物抑制硫氧还蛋白还原酶（TrxR）的能力，TrxR 是金诺芬的潜在主要靶标：总的来说，金化合物比相应的银化合物更能有效地抑制 TrxR，这可能是由于金与活性位点硒代半胱氨酸残基的结合更强所致。这些结果强调，金诺芬的硫代糖配体对于细胞毒性不是必需的，而金属中心（金/银）的性质在其调节中起着重要作用。此外，在测试化合物的细胞毒性效力与其抑制 TrxR 活性的能力之间发现了相当清晰的相关性，金化合物比银类似物更有效。然而，在用各种金属配合物的半最大抑制浓度处理 A2780 细胞时，测量到的 TrxR 残留活性远高于预期。这些结果表明，必须存在其他细胞毒性机制。讨论了这些结果的意义。
