Depletion of a discrete nuclear glutathione pool by oxidative stress, but not by buthionine sulfoximine. Correlation with enhanced alkylating agent cytotoxicity to human melanoma cells in vitro.
The existence of a distinct pool of glutathione in the nucleus of cultured human melanoma cells was demonstrated. Melanoma cell nuclei contained 13-35 pmol of glutathione/10(6) nuclei, or approximately 0.4-1.3% of the total cellular glutathione. This nuclear glutathione pool resisted depletion by buthionine sulfoximine, an agent that inhibits glutathione synthesis, but was rapidly and reversibly depleted by subtoxic concentrations of Adriamycin plus carmustine, two agents that promote oxidation of glutathione without permitting its regeneration through enzymatic reduction of glutathione disulfide. The ability of Adriamycin plus carmustine to deplete this small but significant pool of glutathione in the cell nucleus may explain why these agents potentiate the cytotoxic effects of the DNA-alkylating agent melphalan to a much higher degree than does buthionine sulfoximine at concentrations that are equipotent in depleting cytosolic glutathione.
Jevtović-Todorović
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Department of Pharmacology, University of Illinois College of Medicine, Chicago 60612.
Guenthner
T M
TM
D019328:Buthionine Sulfoximine; D002330:Carmustine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D005978:Glutathione / Q000031:analogs & derivatives / Q000032:analysis* / Q000096:biosynthesis / Q000378:metabolism; D019803:Glutathione Disulfide; D006801:Humans; D008545:Melanoma; D008558:Melphalan / Q000494:pharmacology*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010084:Oxidation-Reduction; D014407:Tumor Cells, Cultured / Q000187:drug effects
D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D004317:Doxorubicin; D005978:Glutathione; D008558:Melphalan; D002330:Carmustine; D019803:Glutathione Disulfide