Abstract
Unexpectedly, the widely used anticancer agents Cisplatin (Cis-Pt) and Daunorubicin (Dauno) exhibited cell type- and concentration-dependent synergy or antagonism in vitro. We attempted to interpret these effects in terms of the changes elicited by the drugs in the chromatin, the target held primarily responsible for the cytotoxicity of both agents. We measured the effect of Cis-Pt on the levels of Dauno in different cell compartments, the effect of Cis-Pt on Dauno-induced nucleosome eviction, and assessed the influence of Dauno on DNA platination in flow- and laser scanning cytometry as well as in laser ablation-inductively coupled plasma-mass spectrometry assays. We show that the two drugs antagonize each other through a decrease of interstrand crosslinks upon co-treatment with Dauno, and also via the diminished Dauno uptake in the presence of Cis-Pt, and both effects are observed already at low Dauno concentrations. At high Dauno concentrations synergy becomes dominant because histone eviction by Dauno intercalation into the DNA is enhanced in the presence of co-treatment with Cis-Pt. These interactions may have an impact on the efficacy of combination treatment protocols, considering the long retention time of DNA adducts formed by both agents.
Highlights
The widely used anticancer agents Cisplatin (Cis-Pt) and Daunorubicin (Dauno) exhibited cell type- and concentration-dependent synergy or antagonism in vitro
We used the combination index (C.I.) method based on the median-effect principle of the mass-action law[26], performed according to Chou-Talalay, to determine the mode of drug interaction
In sharp contrast with the Jurkat cells, in HeLa cells antagonism was observed (C.I. > 1) at the subtoxic Dauno concentration range of 0.3–1.8 μM, and synergism (C.I. < 1) at toxic Dauno concentrations ranging between 3–12 μM, using 40 μM Cis-Pt (Fig. 1 and supplementary Table 2)
Summary
The widely used anticancer agents Cisplatin (Cis-Pt) and Daunorubicin (Dauno) exhibited cell type- and concentration-dependent synergy or antagonism in vitro. Cis-Pt-elicited crosslinks may fix internucleosomal DNA in constrained conformation antagonizing intercalation In view of these complexities, we set out to determine how the Dauno evoked changes in chromatin structure and DNA topology affect the formation of Cis-Pt-DNA adducts, and how Cis-Pt influences Dauno uptake and binding. Quantitative laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) spot analysis was applied for the determination of Pt (at Ghent University, Belgium), yielding absolute numbers for total Cis-Pt-DNA adducts and ICLs per nucleus. These studies were performed in an experimental system where Dauno and Cis-Pt either antagonize or synergize each other in a cell-type and concentration dependent manner
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