Indomethacin overcomes doxorubicin resistance by decreasing intracellular content of glutathione and its conjugates with decreasing expression of gamma-glutamylcysteine synthetase via promoter activity in doxorubicin-resistant leukemia cells.
Drug resistance continues to be a serious problem in cancer therapy. We investigated whether indomethacin, which inhibits cyclooxygenases, is able to overcome doxorubicin resistance in K562/ADR leukemia cells. Indomethacin at 10 microM increased the cytotoxicity of doxorubicin and vincristine in K562/ADR cells. Intracellular glutathione content was elevated in K562/ADR cells. Indomethacin treatment decreased glutathione content and glutathione-conjugates in K562/ADR cells. Increased expression of gamma-glutamylcysteine synthetase (gamma-GCS) was observed in K562/ADR cells, but this expression was decreased by indomethacin treatment. The activity of the gamma-GCS promoter from K562/ADR cells decreased after indomethacin treatment in MDA231 cells. These data strongly suggest that the cyclooxygenase inhibitor indomethacin increases the cytotoxicity of doxorubicin by decreasing the intracellular contents of glutathione and its conjugates with decreasing expression of gamma-GCS by inhibiting gamma-GCS promoter activity.
Asano
Takeshi
T
Department of Pediatrics, Nippon Medical School, Chiba Hokusoh Hospital, Inba-Gun, Chiba, Japan. vff13540@nifty.ne.jp
Tsutsuda-Asano
Arisa
A
Fukunaga
Yoshitaka
Y
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D017931:DNA Primers; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D020014:K562 Cells; D007938:Leukemia / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013379:Substrate Specificity
D000970:Antineoplastic Agents; D017931:DNA Primers; D004317:Doxorubicin; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D007213:Indomethacin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; C421109:multidrug resistance-associated protein 1