Effect of Glutathione Depletion on Cisplatin Resistance in Cancer Cells Transfected with the γ‐Glutamylcysteine Synthetase Gene

Overexpression of the human γ‐glutamylcysteine synthetase (γ‐GCS) gene resulted in cisplatin resistance with an increased glutathione (GSH) content, increased ATP‐dependent glutatbione S‐conjugate export pump (GS‐X pump) activity and decreased platinum accumulation in human lung cancer cells transfected with 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.