Cisplatin-induced endoreduplication in CHO cells: DNA damage and inhibition of topoisomerase II.

Abstract

It has been proposed that polyploid cells that arise during a variety of pathological conditions and as a result of exposure to genotoxicants, typically in the liver, become aneuploid through genetic instability. Aneuploidy contributes to, or even drives, tumour development. We have assessed the capacity of the drug cisplatin, one of the most commonly used compounds for the treatment of malignancies, to induce endoreduplication, a particular type of polyploidy, in cultured Chinese hamster AA8 cells. Taking into account that any interference with DNA topoisomerase II (topo II) function leads to endoreduplication, we have found that treatment of the cells with this platinum compound results in a dose-dependent inhibition of the catalytic activity of the enzyme. These observations are discussed on the basis of a possible dual action of cisplatin leading to a combined negative effect on normal segregation of chromosomes. On the one hand, through the drug capacity to efficiently inhibiting the catalytic activity of topo II itself and, on the other hand, as a consequence of changes in DNA such as base modifications and cross-links that result from cisplatin treatment, likely leading to a lack of recognition/binding of DNA by the enzyme. These observations support a model in which the involvement of topo II in different pathways leading to induced endoreduplication has been proposed, and seem to bear significance as to the possible origin of the development of secondary tumours as a result of cisplatin treatment of primary malignancies.