Document Detail

Different mechanisms for gamma-glutamyltransferase-dependent resistance to carboplatin and cisplatin.
MedLine Citation:
PMID:  12906924     Owner:  NLM     Status:  MEDLINE    
In this work, we investigated the effect of gamma-glutamyltransferase (GGT) overexpression on cell viability after carboplatin treatment and compared with cisplatin. Carboplatin challenge of HeLa cells induced GGT and glutamate-cystine ligase (GCL) activities by 2- and 1.4-fold, respectively and concomitantly increased the intracellular reduced glutathione (GSH) level (1.5-fold). To study the role of GGT, HeLa-GGT cells, a stably transfected cell line overexpressing GGT (120-150 mU/mg protein) and the parental HeLa cells (10-15 mU/mg protein) were used. Both cell lines exhibited comparable viability (IC(50) approximately 150 microM) after carboplatin treatment when cultured in standard (250 microM cystine) medium. Culture in low (50 microM) cystine medium resulted in a dramatic decrease (approximately 90%) of the intracellular GSH level and to a 2.5-fold increase of carboplatin cytotoxicity (IC(50) approximately 60 microM). When GSH (50 microM) was included in the culture medium, only HeLa-GGT cells exhibited increased resistance to carboplatin. Using partially purified GGT from HeLa-GGT cells, we show that cisplatin forms adducts with cysteinylglycine, depending only on GGT activity whereas carboplatin did not efficiently react with cysteinylglycine. Thus, in this model system, GGT activity can affect platinum drugs cytotoxocity by two different ways: cisplatin can be detoxified extracellularly after reaction with the -SH group of cysteinylglycine; in the case of carboplatin, the supply of GSH precursors, initiated by GGT, increases the intracellular level of the tripeptide and provides enhanced defensive mechanisms to the cell.
Sandrine Daubeuf; Diane Balin; Pierre Leroy; Athanase Visvikis
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biochemical pharmacology     Volume:  66     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2003 Aug 
Date Detail:
Created Date:  2003-08-08     Completed Date:  2003-11-17     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  595-604     Citation Subset:  IM    
Laboratoire Thiols et Fonctions Cellulaires, Faculté de Pharmacie, Université Henri Poincaré, Nancy 1, 30 rue Lionnois, 54000 Nancy, France.
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MeSH Terms
Antineoplastic Agents / pharmacology*
Carboplatin / metabolism,  pharmacology*
Cisplatin / metabolism,  pharmacology*
Drug Resistance, Neoplasm
Glutamate-Cysteine Ligase / metabolism
Glutathione / analysis
Hela Cells
gamma-Glutamyltransferase / physiology*
Reg. No./Substance:
0/Antineoplastic Agents; 15663-27-1/Cisplatin; 41575-94-4/Carboplatin; 70-18-8/Glutathione; EC; EC Ligase

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