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Biochem Biophys Res Commun. 1995 Nov 2;216(1):258-64.

Gamma-glutamylcysteine synthetase gene overexpression results in increased activity of the ATP-dependent glutathione S-conjugate export pump and cisplatin resistance.

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1
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan.

Abstract

The ATP-dependent glutathione S-conjugate export pump (GS-X pump) has been suggested to play a role in the mechanism of cisplatin resistance. The purpose of this study was to determine the relationship between intracellular glutathione (GSH) levels and GS-X pump activity and whether GS-X pump overexpression results in cisplatin resistance. We transfected the human gamma-glutamylcysteine synthetase (gamma-GCS) gene into a human small-cell lung cancer cell line, SBC-3, producing SBC-3/GCS. The intracellular GSH content of SBC-3/GCS was twice that of the parental line, its GS-X pump activity was significantly enhanced and cellular cisplatin accumulation decreased. SBC-3/GCS showed higher resistance (relative resistance value of 7.4) to cisplatin than the parental line SBC-3. These data indicate that gamma-GCS gene overexpression induces cellular cisplatin resistance associated with increases in both the GSH content and GS-X pump activity, resulting in reduced cisplatin accumulation. In conclusion, GS-X pump expression is related to cellular GSH metabolism and involved in cisplatin resistance.

PMID:
7488097
DOI:
10.1006/bbrc.1995.2618
[Indexed for MEDLINE]

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