Effect of glutathione depletion on cisplatin resistance in cancer cells transfected with the gamma-glutamylcysteine synthetase gene.
Overexpression of the human gamma-glutamylcysteine (gamma-GCS) gene resulted in cisplatin resistance with an increased glutathione (GSH) content, increased ATP-dependent glutathione S-conjugate export pump (GS-X pump) activity and decreased platinum accumulation in human lung cancer cells transfected with a gamma-GCS cDNA expression vector, 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 gamma-GCS-transfected cell line, SBC-3/GCS. In the presence of 10 microM 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.
Kurokawa
H
H
Pharmacology Division, National Cancer Center Research Institute, Tokyo.
Nishio
K
K
Ishida
T
T
Arioka
H
H
Fukuoka
K
K
Nomoto
T
T
Fukumoto
H
H
Yokote
H
H
Saijo
N
N
D019881:Aminoacyltransferases; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000378:metabolism*; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D002945:Cisplatin / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D026901:Membrane Transport Proteins; D010458:Peptidyl Transferases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D026901:Membrane Transport Proteins; C086860:glutathione transporter; D019328:Buthionine Sulfoximine; D019881:Aminoacyltransferases; D010458:Peptidyl Transferases; C093784:glutathione gamma-glutamylcysteinyltransferase; D005978:Glutathione; D002945:Cisplatin