Influence of reducing agents on the cytotoxic activity of platinum(iv) complexes: induction of G2/M arrest, apoptosis and oxidative stress in A2780 and cisplatin resistant A2780cis cell lines

Abstract

The concept of PtIV 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. PtIV 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 PtIV metal centre have been performed so far. Herein, we investigated a set of PtIV 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 PtIV 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 PtIV 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 PtIV complexes.