Pichler Verena, Göschl Simone, Schreiber-Brynzak Ekaterina, Jakupec Michael A, Galanski Markus, Keppler Bernhard K
University of Vienna, Faculty of Chemistry, Institute of Inorganic Chemistry, Waehringer Strasse 42, 1090 Vienna, Austria.
Metallomics. 2015 Jul;7(7):1078-90. doi: 10.1039/c5mt00116a.
The concept of Pt(IV) prodrug design is one advanced strategy to increase the selectivity for cancer cells and to reduce systemic toxicity in comparison to established platinum-based chemotherapy. Pt(IV) complexes are thought to be activated by reduction via physiological reductants, such as ascorbic acid or glutathione. Nevertheless, only few investigations on the link between the reduction rate, which is influenced by the reductant, and the ligand sphere of the Pt(IV) metal centre have been performed so far. Herein, we investigated a set of Pt(IV) compounds with varying rates of reduction with respect to their cytotoxicity and drug accumulation in A2780 and A2780cis ovarian cancer cell lines, their influence on the cell cycle, efficiency of triggering apoptosis, and ability to interfere with plasmid DNA (pUC19). The effects caused by Pt(IV) compounds were compared without or with extracellularly added ascorbic acid and glutathione (or its precursor N-acetylcysteine) to gain understanding of the impact of increased levels of the reductant on the activity of such complexes. Our results demonstrate that reduction is required prior to plasmid interaction. Furthermore, the rate of reduction is crucial for the efficiency of this set of Pt(IV) compounds. The substances that are reduced least likely showed similar performances, whereas the fastest reducing substance was negatively affected by an increased extracellular level of reducing agents, with reduced cytotoxicity and lower efficiency in inducing apoptosis and G2/M arrest. These results confirm the connection between reduction and activity, and prove the strong impact of the reduction site on the activity of Pt(IV) complexes.
与已有的铂类化疗药物相比，铂（IV）前药设计理念是一种提高癌细胞选择性并降低全身毒性的先进策略。铂（IV）配合物被认为可通过生理还原剂（如抗坏血酸或谷胱甘肽）还原而激活。然而，迄今为止，关于受还原剂影响的还原速率与铂（IV）金属中心配体球之间的联系，仅有少量研究。在此，我们研究了一组还原速率不同的铂（IV）化合物，考察它们对A2780和A2780cis卵巢癌细胞系的细胞毒性、药物积累、对细胞周期的影响、引发凋亡的效率以及干扰质粒DNA（pUC19）的能力。在不添加或添加细胞外抗坏血酸和谷胱甘肽（或其前体N - 乙酰半胱氨酸）的情况下，比较铂（IV）化合物所产生的效应，以了解还原剂水平升高对这类配合物活性的影响。我们的结果表明，在与质粒相互作用之前需要进行还原。此外，还原速率对于这组铂（IV）化合物的效率至关重要。还原可能性最小的物质表现出相似的性能，而还原最快的物质受到细胞外还原剂水平升高的负面影响，细胞毒性降低，诱导凋亡和G2/M期阻滞的效率也降低。这些结果证实了还原与活性之间的联系，并证明了还原位点对铂（IV）配合物活性的强烈影响。
