Glutathione related enzymes in cis-diamminedichloroplatinum (II)-sensitive and-resistant human ovarian carcinoma cells

A cis-diamminedichloroplatinum (II) (CDDP)-resistant cell line (NOS2CR) demonstrated 7.4-fold greater resistance to CDDP compared with the parental cell line (NOS2) established from a patient with serous cystadenocarcinoma of the ovary. We investigated the role of enzyme systems associated with glutathione (GSH) in these cell lines. The GSH content was almost identical in both cell lines. Preincubation with 50 microM DL-buthionine-S, R-sulfoximine (BSO), an inhibitor of gamma-glutamyl cysteine synthetase, for 24 hr reduced the IC50 in both NOS2 and NOS2CR cells. Glutathione-S-transferase pi (GST-pi) activity and mRNA level in NOS2CR cells were higher than in NOS2 cells. However, gamma-glutamyltranspeptidase (GGT) activity in NOS2CR cells was 2.4-fold less than in NOS2 cells. The GST activity and mRNA level in both cell lines were constant when the cells were exposed to CDDP. Exposure to CDDP for 48 hr increased the GGT mRNA level 4.4 and 1.8 times in NOS2 and NOS2CR cells, respectively, compared with no exposure. By exposure to CDDP for 48 hr, the GGT activities in NOS2 and NOS2CR cells were increased 1.6-and 2.5-fold, respectively, compared with no exposure. The above data provide the first evidence that GGT activity and GGT mRNA are induced by CDDP in human carcinoma cell lines.