Regulation of gamma-glutamyltransferase in cisplatin-resistant and -sensitive colon carcinoma cells after acute cisplatin and oxidative stress exposures

Glutathione plays an important role in drug resistance of tumor cells and i n their ability to resist oxidative stress. Improved salvage of glutathione can be obtained through increased activity of gamma-glutamyltransferase (G GT), which is of importance in the maintenance of cellular glutathione home ostasis, We investigated the regulation of GGT in 2 cisplatin-resistant and 1 cisplatin-sensitive colon carcinoma cell lines. Enzyme activity was indu ced in all 3 cell lines after acute exposure to cisplatin, The elevation wa s significantly higher in sensitive cells (3.3-fold) than in resistant (1.6 - to 1.7-fold) cells. Exposure of cells to oxidative stress generated by me nadione also resulted in enzyme induction but only in cisplatin-sensitive c ells. Addition of anti-oxidants had different effects on the 2 inductions: N-acetylcysteine blocked the induction of both cisplatin and menadione, whe reas catalase and glutathione-ester blocked only the menadione induction. G lutathione depletion alone was not sufficient to induce GGT in these cells. The data show that GGT is regulated by multiple mechanisms during anti-tum or drug treatment and oxidative stress and that reactive oxygen species wer e involved in the menadione, but not cisplatin, induction of the enzyme. In t. J, Cancer 88:464-468, 2000, (C) 2000 Wiley-Liss. Inc.