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 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.

Salidroside, a Chemopreventive Glycoside, Diminishes Cytotoxic Effect of Cisplatin in Vitro

“… found SAL‐induced inhibition of mTOR pathway in bladder cancer cells while minimal effect on the growth of non‐malignant bladder cell line was observed. As shown in our experiments, CDDP can arrest both sensitive A2780 as well as resistant A2780/CP cells in G2/M phase of cell cycle what is in line with findings of several reports published on various human ovarian carcinoma cells . This CDDP‐induced G2/M phase arrest was accompanied by increased level of DNA damage manifested as the reduced migration of DNA into the tails of comets observed by us in the present investigation, by Hunakova et al .…”

Cisplatin resistance in cell models: evaluation of metallomic and biological predictive biomarkers to address early therapy failure

“…10,22 Despite similarities in cell viability with the GM04312 cells, the sensitivity of the A2780 cells to cisplatin cannot be linked to a deficiency of DNA repair. However, it might be related to their higher Pt influx, as described, 27,37,42,43 even for other platinum chemicals, 44 which could be related to high levels of the copper transport protein CTR1, 23 although recently the influence of this type of protein was considered controversial. 45 Nevertheless, since high Pt influx was not accompanied by high levels of induced DNA adducts, the drug effects on cell viability in these A2780 cells must be related to cisplatin activity in the cell cytoplasm, and not specifically related to apoptosis, because the apoptotic cell number did not significantly change at different Pt concentrations.…”

Cancer‐Specific, Intracellular, Reductive Activation of Anticancer PtIV Prodrugs

“…Encouraged by these results, we studied effects of hybrid 8 and controls on human ovarian carcinoma cell line A2780, which is known to be sensitive to cisplatin . First, we investigated the efficiency of prodrug uptake by A2780 cells by using the chromogenic assay for intracellular boron, as was previously described .…”