Rackham Oliver, Nichols Scott J, Leedman Peter J, Berners-Price Susan J, Filipovska Aleksandra
Laboratory for Cancer Medicine, Western Australian Institute for Medical Research and Center for Medical Research, The University of Western Australia, Perth, Western Australia 6000, Australia.
Biochem Pharmacol. 2007 Oct 1;74(7):992-1002. doi: 10.1016/j.bcp.2007.07.022. Epub 2007 Jul 21.
Bis-chelated gold(I) phosphine complexes have shown great potential as anticancer agents, however, their efficacy has been limited by their high toxicity and lack of selectivity for cancer cells. Here, we have investigated the anticancer activity of a new bis-chelated Au(I) bidentate phosphine complex of the novel water soluble ligand 1,3-bis(di-2-pyridylphosphino)propane (d2pypp). We show that this gold complex [Au(d2pypp)(2)]Cl, at submicromolar concentrations, selectively induces apoptosis in breast cancer cells but not in normal breast cells. Apoptosis was induced via the mitochondrial pathway, which involved mitochondrial membrane potential depolarisation, depletion of the glutathione pool and caspase-3 and caspase-9 activation. The gold lipophilic complex was accumulated in mitochondria of cells, driven by the high mitochondrial membrane potential. To address the molecular basis of the observed selectivity between the two cell lines we investigated the effect of the gold complex on the thioredoxin/thioredoxin reductase system in normal and cancer breast cells. We show that [Au(d2pypp)(2)]Cl inhibits the activities of both thioredoxin and thioredoxin reductase and that this effect is more pronounced in the breast cancer cells. This difference may account for the selective cell death seen in the breast cancer cells but not in the normal cells. Our investigation has led to new insights into the mechanism of action of bis-chelated gold(I) diphosphine complexes and their future development as mitochondria targeted chemotherapeutics.
双螯合金（I）膦配合物已显示出作为抗癌剂的巨大潜力，然而，它们的疗效受到其高毒性和对癌细胞缺乏选择性的限制。在此，我们研究了一种新型水溶性配体1,3-双（二-2-吡啶基膦基）丙烷（d2pypp）的新型双螯合金（I）双齿膦配合物的抗癌活性。我们表明，这种金配合物[Au(d2pypp)(2)]Cl在亚微摩尔浓度下选择性地诱导乳腺癌细胞凋亡，而不诱导正常乳腺细胞凋亡。凋亡是通过线粒体途径诱导的，该途径涉及线粒体膜电位去极化、谷胱甘肽池耗竭以及半胱天冬酶-3和半胱天冬酶-9激活。金亲脂性配合物由高线粒体膜电位驱动，积聚在细胞的线粒体中。为了探究两种细胞系之间观察到的选择性的分子基础，我们研究了金配合物对正常和癌性乳腺细胞中硫氧还蛋白/硫氧还蛋白还原酶系统的影响。我们表明，[Au(d2pypp)(2)]Cl抑制硫氧还蛋白和硫氧还蛋白还原酶的活性，并且这种作用在乳腺癌细胞中更为明显。这种差异可能解释了在乳腺癌细胞中而非正常细胞中观察到的选择性细胞死亡。我们的研究为双螯合金（I）二膦配合物的作用机制及其作为线粒体靶向化疗药物的未来发展提供了新的见解。
