Enhanced expression of gamma-glutamylcysteine synthetase and glutathione S-transferase genes in cisplatin-resistant bladder cancer cells with multidrug resistance phenotype.
OBJECTIVE
To elucidate the mechanisms of cisplatin resistance in human bladder cancer.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Kotoh
S
S
Department of Urology and Biochemistry, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Naito
S
S
Yokomizo
A
A
Kohno
K
K
Kuwano
M
M
Kumazawa
J
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D019450:Genes, MDR / Q000235:genetics*; D005721:Glutamate-Cysteine Ligase / Q000096:biosynthesis / Q000235:genetics*; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics*
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D005982:Glutathione Transferase; D005721:Glutamate-Cysteine Ligase; D002945:Cisplatin