title: Effect of glutathione depletion on cisplatin resistance in cancer cells transfected with the gamma-glutamylcysteine synthetase gene.
abstract: 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.
authors.affiliation: Pharmacology Division, National Cancer Center Research Institute, Tokyo.
authors.forename: H
authors.initials: H
authors.lastname: Kurokawa
authors.forename: K
authors.initials: K
authors.lastname: Nishio
authors.forename: T
authors.initials: T
authors.lastname: Ishida
authors.forename: H
authors.initials: H
authors.lastname: Arioka
authors.forename: K
authors.initials: K
authors.lastname: Fukuoka
authors.forename: T
authors.initials: T
authors.lastname: Nomoto
authors.forename: H
authors.initials: H
authors.lastname: Fukumoto
authors.forename: H
authors.initials: H
authors.lastname: Yokote
authors.forename: N
authors.initials: N
authors.lastname: Saijo
mesh_terms: 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
chemical_list: 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