EFFECT OF GLUTATHIONE DEPLETION ON CISPLATIN RESISTANCE IN CANCER-CELLS TRANSFECTED WITH THE GAMMA-GLUTAMYLCYSTEINE SYNTHETASE GENE

Overexpression of the human gamma-glutamylcysteine synthetase (gamma-G CS) gene resulted in cisplatin resistance with an increased glutathion e (GSH) content, increased ATP-dependent glutathione S-conjugate expor t pump (GS-X pump) activity and decreased platinum accumulation in hum an lung cancer cells transfected with a gamma-GCS cDNA expression vect or, as we previously reported. In this study, we examined the effects of buthionine sulfoximine (BSO), a specific inhibitor of gamma-GCS, to determine whether GSH depletion alters cisplatin resistance in a gamm a-GCS-transfected cell line, SBC-3/ GCS. In the presence of 10 mu M BS O 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 c ontent was decreased. These data suggest that the GS-X pump itself inf luences cisplatin resistance, as well as cellular GSH content.