Lack of correlation between cisplatin cytotoxic effect and potential Na, K-adenosine triphosphatase (Na, K-ATPase) activity or intracellular level of glutathione

Abstract

The use of cisplatin as a cancer chemotherapeutic agent is limited by its dose dependent nephrotoxicity. It has been suggested that the differential toxic effects of cisplatin may be related to differences in Na+/K+ ATPase activity or levels of glutathione (GSH). The present study evaluated these possibilities by testing cells from different tissue origins for their sensitivities to cisplatin and the numbers of Na+/K+ ATPase, affinities to ouabain and intracellular glutathione levels. Our results have shown that the cytotoxic effect of cisplatin was in the order of Calu-1>U-138MG>HEK>SK-HEp1>AGS>TL cells. Dissociation contants (K-d) of the different cell lines to ouabain revealed that the U-138MG cells (29 pM) had the highest affinity while the SK-HEp1 cells (123 pM) had the lowest. In addition the most number of ouabain binding sites was detectable on the Calu-1 cells (2.388x10(5)/cell) with the lowest in the U-138MG (5.22x10(4)/cell) cells. Linear regression analysis of these data indicate that there is no correlation between toxicity of cisplatin to the density (p=0.6563) or affinity (p=0.5499) of the Na+/K+ ATPase to ouabain on the responding cells. Nor is there a direct correlation between cisplatin toxicity and the level of intercellular GSH. These results suggest that activity of Na+/K+ ATPase or level of GSH alone is not sufficient to account fbr the differential toxicity of cisplatin nor is it a necessary trait of cisplatin resistance.