Inhibition of gamma-glutamyl transpeptidase activity decreases intracellular cysteine levels in cervical carcinoma.
OBJECTIVE
To determine whether gamma-glutamyl transpeptidase (gamma-GT) is involved in the maintenance of elevated cysteine levels in cervical carcinoma.


METHODS
Four cervical carcinoma cell lines were tested in vitro for cysteine accumulation and gamma-GT levels. The highest and lowest gamma-GT-expressing cell lines were used in in vivo experiments to determine the effect of gamma-GT inhibition on cysteine levels.


RESULTS
Treatment of a series of cervical carcinoma cell lines with acivicin decreased intracellular cysteine concentrations. Cysteine depletion was evident in Me180 cells which had the greatest levels of gamma-GT activity, and had a more pronounced cysteine decrease in medium with glutathione and cysteine concentrations simulating the in vivo situation. Also investigated were the effects of inhibition of gamma-GT activity on intracellular cysteine levels in xenografts grown in severe combined immunodeficient (SCID) mice. With the use of 35 mg/kg of acivicin, gamma-GT activity decreased to basal levels of detection in both tumour types and significant decreases in cysteine levels were seen in the high gamma-GT-expressing tumours (Me180). Thus, inhibition of gamma-GT activity may have therapeutic potential in high-expressing cancers.


CONCLUSIONS
In tumours and cell lines with elevated levels of gamma-GT activity, inhibition of this enzyme led to decreases of cysteine levels.
Ruoso
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Division of Experimental Therapeutics, Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada.
Hedley
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DW
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000503:physiopathology*; D045744:Cell Line, Tumor; D003545:Cysteine / Q000032:analysis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D014183:Transplantation, Heterologous; D002583:Uterine Cervical Neoplasms / Q000503:physiopathology*; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D007555:Isoxazoles; D005723:gamma-Glutamyltransferase; D003545:Cysteine; C006303:acivicin