Apoptosis in human lymphoblastoid cells induced by acivicin, a specific γ glutamyltransferase inhibitor

Abstract

We examined the effects of acivicin, a specific inhibitor of the ectoenzyme gamma-glutamyltransferase (gamma-GT), on gamma-GT activity and apoptosis in 2 human T-lymphoblastoid CEM cell lines, CCRF and VBL-100. In both cell lines, acivicin was found to cause morphological and biochemical changes of apoptosis in a dose-dependent manner. There was a close correlation between inhibition of gamma-GT activity and the emergence of apoptotic cells. However, VBL-100 cells had a 50% higher gamma-GT basal activity than CCRF-CEM cells, their enzyme activity was more inhibited, and, they had a greater apoptotic response to acivicin. The gamma-GT-specific activity in apoptotic/dead cells was also almost totally inhibited, while that of cells that remained alive after 5 days of acivicin treatment was not. These findings confirm that gamma-GT is implicated in the process of apoptosis of CEM cells.

γ-Glutamyltranspeptidase knockout mice as a model for understanding the consequences of diminished glutathione on T cell-dependent immune responses

“…Several studies have demonstrated a correlation between decreased GSH or blocking the activation-induced increase in T cell GSH and increased apoptosis [25][26][27][28][29]. Furthermore, blocking GGT activity with acivicin has also been reported to enhance T cell apoptosis [30]. These relationships suggest that in response to activation, T cells in GGT -/-mice may undergo activation-induced cell death more readily than T cells from wild-type mice, thereby explaining the diminished response to activation.…”

Expression of γ-Glutamyl Transpeptidase Protects Ramos B Cells from Oxidation-induced Cell Death

“…This compound also inhibits other enzymes that utilize glutamine as a substrate, such as those involved in nucleoside biosynthesis (25). Thus, it can contribute to the background level of cell death (26). As seen in Table II, the addition of 50 M GSH to Ramos/X and Ramos/GGT cells cultured in cyst(e)inefree, GSH-free medium was able to prevent cell death in 20 -40% of the Ramos/X cells and 50 -70% of the Ramos/GGT cells.…”

Ectopeptidases in pathophysiology

“…Inhibitors of APN and g-GT induce apoptosis of T and myeloid cell lines. (51,55,62) Unlike in HIV-infected jurkat T cells in which transfection of DPPIV cDNA protects them from apoptosis, (6) engagement of DPPIV in a hepatocarcinoma cell line through DPPIV Ab, delivers a potent apoptotic signal (64) suggesting that DPPIV exerts opposite functions in different cell contexts.…”