Drug resistance continues to be a serious problem in cancer therapy. We investigated whether indomethacin, which inhibited cyclooxygenases, would overcome doxorubicin resistance in K562/ADR leukemia cells. Indomethacin at 3μg/ml increased the cytotoxicity of doxorubicin as well as vincristine in K562/ADR. Intracellular glutathione content was increased in K562/ADR cell. Indomethacin treatment decreased glutathione content and glutathione conjugates in K562/ADR cells. Increased expression of γ-glutamylcysteine synthetase (γ-GCS) was observed in K562/ADR cells, but this expression was decreased by indomethacin treatment. The activity of the γ-GCS promoter decreased after indomethacin treatment in Hela cells. These data strongly suggest that the cyclooxygenase inhibitor indomethacin increased the cytotoxicity of doxorubicin by decrease intracellular glutathione content along with decrease expression of γ-GCS through inhibition of γ-GCS promoter activity.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]