Inhibition of gamma-glutamyl transpeptidase activity decreases intracellular cysteine levels in cervical carcinoma

Abstract

Purpose: 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.