Augmentation of cisplatin sensitivity in cisplatin-resistant human bladder cancer cells by modulating glutathione concentrations and glutathione-related enzyme activities

Abstract

OBJECTIVES: To investigate the roles of glutathione and glutathione-S-transferase (GST) in cisplatin-resistance mechanisms in human bladder cancer, by using glutathione-depleting or GST-blocking agents. MATERIALS AND METHODS: Cisplatin-resistant human bladder cancer cell lines were established by continuous exposure of T24 cells to increasing concentrations of cisplatin. Buthionine sulphoximine (BSO), ethacrynic acid and indomethacin were used to deplete glutathione or block GST. Intracellular glutathione content, GST activity and cisplatin cytotoxicity were determined after exposing parental and drug-resistant cell lines to these agents. RESULTS: Intracellular glutathione content and GST activity were significantly decreased, and cisplatin cytotoxicity significantly enhanced, in both parental and resistant cell lines by glutathione-depleting or GST-blocking agents. However, the resistance of cisplatin-resistant cell lines did not fully recover to that of the parental cells with combined BSO and indomethacin. CONCLUSIONS: Both increased glutathione content and GST activity are significant in the cisplatin resistance of human bladder tumour cells. Because BSO, ethacrynic acid and indomethacin caused a partial recovery of resistance in the cisplatin-resistant cell line, further studies are needed to investigate their efficacy for treating patients with metastatic bladder carcinoma resistant to cisplatin.