Casini Angela, Hartinger Christian, Gabbiani Chiara, Mini Enrico, Dyson Paul J, Keppler Bernard K, Messori Luigi
Department of Chemistry, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
J Inorg Biochem. 2008 Mar;102(3):564-75. doi: 10.1016/j.jinorgbio.2007.11.003. Epub 2007 Nov 28.
Gold(III) compounds constitute an emerging class of biologically active substances, of special interest as potential anticancer agents. During the past decade a number of structurally diverse gold(III) complexes were reported to be acceptably stable under physiological-like conditions and to manifest very promising cytotoxic effects against selected human tumour cell lines, making them good candidates as anti-tumour drugs. Some representative examples will be described in detail. There is considerable interest in understanding the precise biochemical mechanisms of these novel cytotoxic agents. Based on experimental evidence collected so far we hypothesize that these metallodrugs, at variance with classical platinum(II) drugs, produce in most cases their growth inhibition effects through a variety of "DNA-independent" mechanisms. Notably, strong inhibition of the selenoenzyme thioredoxin reductase and associated disregulation of mitochondrial functions were clearly documented in some selected cases, thus providing a solid biochemical basis for the pronounced proapoptotic effects. These observations led us to investigate in detail the reactions of gold(III) compounds with a few model proteins in order to gain molecular-level information on the possible interaction modes with possible protein targets. Valuable insight on the formation and the nature of gold-protein adducts was gained through ESI MS (electrospray ionization mass spectrometry) and spectrophotometric studies of appropriate model systems as it is exemplified here by the reactions of two representative gold(III) compounds with cytochrome c and ubiquitin. The mechanistic relevance of gold(III)-induced oxidative protein damage and of direct gold coordination to protein sidechains is specifically assessed. Perspectives for the future of this topics are briefly outlined.
金（III）化合物构成了一类新兴的生物活性物质，作为潜在的抗癌剂具有特殊意义。在过去十年中，据报道许多结构多样的金（III）配合物在类似生理条件下具有可接受的稳定性，并对选定的人类肿瘤细胞系表现出非常有前景的细胞毒性作用，使其成为抗肿瘤药物的良好候选者。将详细描述一些代表性例子。人们对了解这些新型细胞毒性剂的确切生化机制有着浓厚兴趣。根据目前收集的实验证据，我们假设这些金属药物与经典的铂（II）药物不同，在大多数情况下通过多种“不依赖DNA”的机制产生生长抑制作用。值得注意的是，在一些选定的案例中，硒酶硫氧还蛋白还原酶受到强烈抑制以及线粒体功能的相关失调已得到明确记录，从而为明显的促凋亡作用提供了坚实的生化基础。这些观察结果促使我们详细研究金（III）化合物与一些模型蛋白的反应，以便获得关于与可能的蛋白质靶点相互作用模式的分子水平信息。通过电喷雾电离质谱（ESI MS）和对适当模型系统的分光光度研究，对金 - 蛋白加合物的形成和性质有了宝贵的见解，这里以两种代表性金（III）化合物与细胞色素c和泛素的反应为例进行说明。特别评估了金（III）诱导的氧化蛋白损伤以及金与蛋白侧链直接配位的机制相关性。简要概述了该主题的未来展望。
