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

Cancer Chemother Pharmacol. 2009 Sep;64(4):715-21. doi: 10.1007/s00280-008-0920-6. Epub 2009 Jan 20.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Base Sequence
  • DNA Primers
  • Doxorubicin / pharmacology*
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Glutamate-Cysteine Ligase / genetics
  • Glutamate-Cysteine Ligase / metabolism*
  • Glutathione / metabolism*
  • Humans
  • Indomethacin / pharmacology*
  • K562 Cells
  • Leukemia / enzymology
  • Leukemia / metabolism
  • Leukemia / pathology
  • Multidrug Resistance-Associated Proteins / genetics
  • Promoter Regions, Genetic*
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Substrate Specificity

Substances

  • Antineoplastic Agents
  • DNA Primers
  • Multidrug Resistance-Associated Proteins
  • RNA, Messenger
  • Doxorubicin
  • Glutamate-Cysteine Ligase
  • Glutathione
  • Indomethacin
  • multidrug resistance-associated protein 1