N‐Acetylcysteine Modifies cis‐Dichlorodiammineplatinum‐induced Effects in Bladder Cancer Cells

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Abstract
We previously demonstrated a role of reactive oxygen species (ROS) in cytotoxicity induced by cis‐dichlorodiammineplatinum (CDDP) in combination with glutathione (GSH) depletors in bladder cancer cells. However, the relationship between CDDP and ROS is still unclear, although many mechanisms of drug resistance have been well characterized. The present study was undertaken to investigate the effects of N‐acetylcysteine (NAC), a GSH precursor, on the CDDP‐induced effects in bladder cancer cells (KU1). The cytotoxic effects of CDDP were significantly blunted by NAC (1 mM) in KU1 cells. The IC50 of CDDP only (10.2±1.2 μM) is significantly lower than that of CDDP with NAC (IC50: 20.3±1.6 μM) in KU1 cells. NAC also significantly increased the intracellular concentration of GSH in KU1 cells (37.2±1.6 nmol/106 cells), compared to controls (15.9±7.6 nmol/106 cells). While CDDP produced a significant increase in ROS as measured in terms of dichlorofluorescein (DCF) production in KU1 cells in a time‐dependent manner, pretreatment with NAC significantly reduced CDDP‐induced intracellular DCF in KU1 cells. Moreover, TdT‐mediated dUTP‐biotin nick‐end labeling (TUNEL) assay showed that CDDP‐induced apoptosis (31.1±3.8%) was significantly inhibited by pretreatment with NAC in KU1 cells (11.2±2.6%). These results demonstrated that NAC scavenges CDDP‐induced ROS and inhibits CDDP‐induced cytotoxicity, suggesting that ROS mediate the CDDP‐induced cytotoxicity in bladder cancer cells.
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