Increased Glutathione Level Is not Involved in Enhanced Bleomycin Sensitivity in Cisplatin-resistant 2780^CP Cells

Abstract

The cytotoxic activity of bleomycin (BLM) was evaluated in cisplatin (CDDP)-sensitive (A2780) and - resistant (2780^CP) human ovarian cancer cells, and the mechanism of increased antitumor activity of BLM in the 2780^CP cells was investigated. Compared with the A2780 cells, the 2780^CP cells exhibited a 4.5-fold increase in resistance to CDDP, but were 4.0-fold more sensitive to BLM. The cellular glutathione (GSH) levels in the 2780^CP cells were significantly higher than those in the A2780 cells, however, GSH depletion in the 2780^CP cells below the levels in the A2780 cells by using buthionine-[S,R]-sulfoximine (BSO) did not affect the sensitivity to BLM. BLM decreased 5-bromo-2′-deoxyuridine (BrdU) incorporation after 24-h exposure by 27.5%-90% compared to that of the untreated control at BLM doses of 25-500 ng/ml in the 2780^CP cells, but only by 1.5%-45.8% in the A2780 cells. Furthermore, in the 2780^CP cells, the percentage of S-phase cells markedly decreased, with an increase in G₂/M-phase cells as determined by flow cytometry after exposure to BLM. The enhanced cytotoxity of BLM in CDDP-resistant 2780^CP cells could be attributed to BLM-induced G₂/M accumulation and significantly inhibited DNA synthesis, not to increased cellular GSH levels.