A glutathione depletion selectively imposed on mu glutathione S-transferase overproducing cells increases nitrogen mustard toxicity.
Glutathione (GSH) contributes to the detoxification of anticancer drugs through the operation of specific glutathione S-transferases (GST) and innate, or acquired, overexpression of this enzyme family has been frequently observed in tumor cell lines. In the GMA32 line of Chinese hamster fibroblasts, we showed that GSH starvation produced by exposing cells to buthionine sulfoximine (BSO) increased the toxicity of chlorambucil and melphalan, but not that of N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), cisplatine and doxorubicin. This indicates that efficient mechanisms of detoxification using GSH operate for chlorambucil and melphalan, but not for the other drugs in these cells. We then showed that GSH depletion could be selectively and transiently induced in the mu GST overexpressing cell line derived from GMA32, HC474, by exposing cells to substrates specific to the overexpressed isozyme. Exposing cells to such a substrate, trans-stilbene oxide, does not alter the sensibility of GMA32 cells to melphalan and chlorambucil, but increases that of HC474 cells to these drugs, to an extent comparable to that obtained with BSO. This observation highlights the possibility of exploiting GST overexpression, a frequent feature of tumor cells, to selectively sensitize these undesirable cells to anticancer drugs.
Unité de Génétique Somatique, URA CNRS 361, Institut Pasteur, Paris, France.
C
C
Lunel-Orsini
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G
Buttin
B R
BR
De Saint Vincent
D000818:Animals; D019328:Buthionine Sulfoximine; D002330:Carmustine / Q000633:toxicity; D002460:Cell Line / Q000187:drug effects; D002470:Cell Survival; D002945:Cisplatin / Q000633:toxicity; D006224:Cricetinae; D003412:Cricetulus; D004317:Doxorubicin / Q000633:toxicity; D005978:Glutathione / Q000172:deficiency*; D005982:Glutathione Transferase / Q000096:biosynthesis* / Q000235:genetics; D008658:Inactivation, Metabolic; D008466:Mechlorethamine / Q000633:toxicity*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology
D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D008466:Mechlorethamine; D004317:Doxorubicin; D005982:Glutathione Transferase; D005978:Glutathione; D002945:Cisplatin; D002330:Carmustine