Issue 3, 2017

Comparative studies of oxaliplatin-based platinum(iv) complexes in different in vitro and in vivo tumor models

Abstract

Using platinum(IV) prodrugs of clinically established platinum(II) compounds is a strategy to overcome side effects and acquired resistances. We studied four oxaliplatin-derived platinum(IV) complexes with varying axial ligands in various in vitro and in vivo settings. The ability to interfere with DNA (pUC19) in the presence and absence of a reducing agent (ascorbic acid) was investigated in cell-free experiments. Cytotoxicity was compared under normoxic and hypoxic conditions in monolayer cultures and multicellular spheroids of colon carcinoma cell lines. Effects on the cell cycle were investigated by flow cytometry, and the capacity of inducing apoptosis was confirmed by flow cytometry and Western blotting. The anti-cancer activity of one complex was studied in vivo in immunodeficient and immunocompetent mice, and the platinum levels in various organs and the tumor after treatment were quantified. The results demonstrate that modification of the axial ligands can improve the cytotoxic potency. The complexes are able to interfere with plasmid DNA, which is enhanced by co-incubation with a reducing agent, and cause cell cycle perturbations. At higher concentrations, they induce apoptosis, but generate only low levels of reactive oxygen species. Two of the complexes increase the life span of leukemia (L1210) bearing mice, and one showed effects similar to oxaliplatin in a CT26 solid tumor model, despite the low platinum levels in the tumor. As in the case of oxaliplatin, activity in the latter model depends on an intact immune system. These findings show new perspectives for the development of platinum(IV) prodrugs of the anticancer agent oxaliplatin, combining bioreductive properties and immunogenic aspects.

Graphical abstract: Comparative studies of oxaliplatin-based platinum(iv) complexes in different in vitro and in vivo tumor models

Supplementary files

Article information

Article type
Paper
Submitted
05 okt 2016
Accepted
31 jan 2017
First published
16 feb 2017
This article is Open Access
Creative Commons BY license

Metallomics, 2017,9, 309-322

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