Enhanced Expression of gamma/Glutamylcysteine Synthetase and Glutathione S-transferase Genes in Cisplatin-Resistant Bladder Cancer Cells with Multidrug Resistance Phenotype

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Abstract
To elucidate the mechanisms of cisplatin resistance in human bladder cancer. After continuous exposure of KK47 cells to cisplatin, two resistant sublines, KK47/DDP10 and KK47/DDP20 were established. The glutathione content, glutathione S-transferase activity, and intracellular platinum concentration were measured while the expression of various drug resistance-related genes was examined. KK47/DDP10 and KK47/DDP20 were respectively 9.3- and 18.7-fold more resistant to cisplatin than KK47, and also showed multidrug resistance. Decreased intracellular drug accumulation, increased glutathione content, elevated glutathione S-transferase activity, and an overexpression of gamma-glutamylcysteine synthetase and glutathione S-transferase pi genes were observed in the resistant sublines. Multiple mechanisms, including decreased drug accumulation, increased intracellular glutathione and glutathione S-transferase pi, may contribute to the acquisition of cisplatin resistance in human bladder cancer.