Wang Shaoyu, Higgins Vincent J, Aldrich-Wright Janice R, Wu Ming J
School of Biomedical and Health Science, University of Western Sydney, Locked Bag 1797, Sydney, Penrith NSW 2751 Australia ; School of Medicine, University of Western Sydney, Locked Bag 1797, Sydney, Penrith NSW 2751 Australia.
J Chem Biol. 2012 Apr;5(2):51-61. doi: 10.1007/s12154-011-0070-x. Epub 2011 Dec 6.
Platinum-based DNA metallointercalators are structurally different from the covalent DNA binders such as cisplatin and its derivatives but have potent in vitro activity in cancer cell lines. However, limited understanding of their molecular mechanisms of cytotoxic action greatly hinders their further development as anticancer agents. In this study, a lead platinum-based metallointercalator, (5,6-dimethyl-1,10-phenanthroline) (1S,2S-diaminocyclohexane)platinum(II) (56MESS) was found to be 163-fold more active than cisplatin in a cisplatin-resistant cancer cell line. By using transcriptomics in a eukaryotic model organism, yeast Saccharomyces cerevisiae, we identified 93 genes that changed their expressions significantly upon exposure of 56MESS in comparison to untreated controls (p ≤ 0.05). Bioinformatic analysis of these genes demonstrated that iron and copper metabolism, sulfur-containing amino acids and stress response were involved in the cytotoxicity of 56MESS. Follow-up experiments showed that the iron and copper concentrations were much lower in 56MESS-treated cells compared to controls as measured by inductively coupled plasma optical emission spectrometry. Deletion mutants of the key genes in the iron and copper metabolism pathway and glutathione synthesis were sensitive to 56MESS. Taken together, the study demonstrated that the cytotoxic action of 56MESS is mediated by its ability to disrupt iron and copper metabolism, suppress the biosynthesis of sulfur-containing amino acids and attenuate cellular defence capacity. As these mechanisms are in clear contrast to the DNA binding mechanism for cisplatin and its derivative, 56MESS may be able to overcome cisplatin-resistant cancers. These findings have provided basis to further develop the platinum-based metallointercalators as anticancer agents.
The online version of this article (doi:10.1007/s12154-011-0070-x) contains supplementary material, which is available to authorized users.
基于铂的DNA金属嵌入剂在结构上不同于顺铂及其衍生物等共价DNA结合剂，但在癌细胞系中具有强大的体外活性。然而，对其细胞毒性作用分子机制的了解有限，极大地阻碍了它们作为抗癌药物的进一步开发。在本研究中，一种先导基于铂的金属嵌入剂，(5,6-二甲基-1,10-菲咯啉)(1S,2S-二氨基环己烷)铂(II) (56MESS)，在顺铂耐药癌细胞系中被发现比顺铂活性高163倍。通过在真核模式生物酿酒酵母中使用转录组学，我们鉴定出93个基因，与未处理对照相比，在暴露于56MESS后其表达发生了显著变化（p≤0.05）。对这些基因的生物信息学分析表明，铁和铜代谢、含硫氨基酸和应激反应参与了56MESS的细胞毒性。后续实验表明，通过电感耦合等离子体发射光谱法测量，与对照相比，56MESS处理细胞中的铁和铜浓度要低得多。铁和铜代谢途径以及谷胱甘肽合成中的关键基因缺失突变体对56MESS敏感。综上所述，该研究表明56MESS的细胞毒性作用是由其破坏铁和铜代谢、抑制含硫氨基酸生物合成以及减弱细胞防御能力的能力介导的。由于这些机制与顺铂及其衍生物的DNA结合机制明显不同，56MESS可能能够克服顺铂耐药癌症。这些发现为进一步开发基于铂的金属嵌入剂作为抗癌药物提供了依据。
本文的在线版本（doi:10.1007/s12154-011-0070-x）包含补充材料，授权用户可以获取。
