Effect of glutathione depletion on cisplatin resistance in cancer cells transfected with the γ-glutamylcysteine synthetase gene

Abstract

Overexpression of the human γ-glutamylcysteine synthetase (γ-GCS) gene resulted in cisplatin resistance with an increased glutathione (GSH) content, increased ATP-dependent glutathione S-conjugate export pump (GS-X pump) activity and decreased platinum accumulation in human lung cancer cells transfectedwith a γ-GCS cDNA expression vector, as we previously reported. In this study, we examined the effects of buthionine sulfoximine (BSO), a specific inhibitor of γ-GCS, to determine whether GSH depletion alters cisplatin resistance in a γ-GCS-transfected cell line, SBC-3/GCS. In the presence of 10 μM BSO for 4 days, SBC-3/GCS still showed resistance to cisplatin, although it was partially reversed. Under these conditions, GS-X pump activity remained up-regulated in spite of low GSH content, and the platinum content was decreased. These data suggest that the GS-X pump itself influences cisplatin resistance, as well as cellular GSH content.