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Indomethacin overcomes doxorubicin resistance by decreasing intracellular content of glutathione and its conjugates with decreasing expression of γ-glutamylcysteine synthetase via promoter activity in doxorubicin-resistant leukemia cells

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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 μM 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 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 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 γ-GCS by inhibiting γ-GCS promoter activity.

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References

  1. Asano T, Zhi C-L, Hayakawa J, Fukunaga Y (2003) Analysis of resistance-related gene expression in doxorubicin resistant leukemia cell line by DNA microarray. Jpn J Pediatr Hematol 17:348–353

    Google Scholar 

  2. Brenner CA, Tam AW, Nelson PA, Engleman EG, Suzuki N, Fry KE, Larrick JW (1989) Message amplification phenotyping (MAPPing): a technique to simultaneously measure multiple mRNAs from small numbers of cells. Bio techniques 7:1096–1103

    CAS  Google Scholar 

  3. Cullen KV, Davey RA, Davey MW (2001) Verapamil-stimulated glutathione transport by the mutidrug resistance-associated protein (MRP1) in leukaemia cells. Biochem Pharmacol 62:417–424

    Article  PubMed  CAS  Google Scholar 

  4. van der Holt B, Lowenberg B, Burnett AK, Knauf WU, Shepherd J, Piccaluga PP, Ossenkoppele GJ, Verhoef GEG, Ferrant A, Crump M, Selleslag D, Theobald M, Fey MF, Vellenga E, Dugan M, Sonneveld P, on behalf of the Dutch-Belgian Hemato-Oncology Cooperative Group and the United Kingdom Medical Council. (2005) The value of the MDR1 reversal agent PSC-833 in addition to daunorubicin and cytarabine in the treatment of elderly patients with previously untreated acute myeloid leukemia (AML), in relation to MDR1 status at diagnosis. Blood 106:2646–2654

    Article  PubMed  Google Scholar 

  5. Iida T, Kijima H, Urata Y, Goto S, Ihara Y, Ola M, Kohno S, Scanlon KJ, Kondo T (2001) Hammerhead ribozyne against γ-glutamylcysteine synthetase sensitizes human colon cancer cells to cisplatin by downregulating both the glutathione synthesis and the expression of multiple drug resistance protein. Cancer Gene Ther 8:803–814

    Article  PubMed  CAS  Google Scholar 

  6. Ishiwaka T, Wright CD, Ishizuka H (1994) GS-X pump is functionally overexpressed in cis-diamminedichloroplatinum(II)-resistant human leukemia HL-60 cells and down-regulated by cell differentiation. J Biol Chem 269:29085–29093

    Google Scholar 

  7. Ishikawa T, Bao J-J, Yamane Y, Akimaru K, Frindrich K, Wright CD, Kuo MT (1996) Coordinated induction of MRP/GS-X pump and γ-glutamylcysteine synthetase by heavy metals in human leukemia cells. J Biol Chem 271:14981–14988

    Article  PubMed  CAS  Google Scholar 

  8. Kartner N, Riordan JR, Ling V (1985) Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. Science 316:820–823

    CAS  Google Scholar 

  9. van der Kolk DM, de Vries EGE, Muller M, Vellenga E (2002) The role of drug efflux pumps in acute myeloid leukemia. Leuk Lymphoma 43:685–701

    Article  PubMed  Google Scholar 

  10. Kundu N, Fulton AM (2002) Selective cyclooxygenase (Cox)-1 or Cox-2 inhibitors control metastatic disease in a murine model of breast cancer. Cancer Res 62:2343–2346

    PubMed  CAS  Google Scholar 

  11. Kruth GD, Belinsky MG (2003) The MRP family of drug efflux pumps. Oncogene 22:7537–7552

    Article  Google Scholar 

  12. Kuo MT, Bao J-J, Curley SA, Ikeguchi M, Johnston DA, Ishikawa T (1996) Frequent coordinated overexpression of the MRP/GS-X pump and γ-glutamylcysteine synthetase genes in human colorectal cancers. Cancer Res 56:3642–3644

    PubMed  CAS  Google Scholar 

  13. Martin F, Pener M-F, Malergue F, Lepidi H, Dessein A, Galland F, de Reggi M, Naquet P, Gharib B (2004) Vanin-1-/- mice show decreased NSAID- and Schistosoma-induced intestinal inflammation associated with higher glutathione stores. J Clin Invest 113:591–597

    PubMed  CAS  Google Scholar 

  14. Matsunaga S, Asano T, Tsutsuda-Asano A, Fukunaga Y (2006) Indomethacin overcomes doxorubicin resistance with inhibiting Multi-drug resistance protein 1 (MRP1). Cancer Chemother Pharmacol 58(3):348–353

    Article  PubMed  CAS  Google Scholar 

  15. Morales A, Miranda M, Sanchez-Reyes A, Colell A, Biete A, Fernandez-Checa JC (1998) Transcriptional regulation of eavy subunit chain of γ-glutamycysteine synthetase by ionizing radiation. FEBS Lett 447:15–20

    Article  Google Scholar 

  16. Noguchi T, Ren X-Q, Aoki S, Igarashi Y, Che X-F, Nakajima Y, Tkahashi H, Mitsuo R, Tsujikawa K, Sumizawa T, Haraguchi M, Kobayashi M, Goto S, Kanehisa M, Aikou T, Akiyama S, Furukawa T (2005) MRP1 mutated in the L0 region transports SN-38 but not leukotriene C4 or estradiol-17 (β-d-glucuronate). Biochem Pharmacol 70:1056–1065

    Article  PubMed  CAS  Google Scholar 

  17. Roller A, Baehr O, Streffer J, Winter S, Heneka M, Deininger M, Meyermann R, Naumann U, Gulbins E, Weller M (1999) Selective potentiation of drug cytotoxicity by NSAID in human glioma cells: the role of Cox-1 and MRP. Biochem Biophys Res Commun 259:600–605

    Article  PubMed  CAS  Google Scholar 

  18. Salerno M, Garnier-Sullerot A (2001) Kinetics of glutathione and daunorubicin efflux from multidrug resistance protein overexpressing small-cell lung cancer cells. Eur J Pharmacol 421:1–9

    Article  PubMed  CAS  Google Scholar 

  19. Sales KJ, Katz AA, Howard B, Soeter RP, Millar RP, Jabbour HN, Soeters RP (2002) Cyclooxygenase-1 is up-regulated in cervical carcinomas: Autocrine/paracrine regulation of cyclooxygenase-2, prostaglandin E receptors, and angiogenic factors by cyclooxygenase-1. Cancer Res 62:424–432

    PubMed  CAS  Google Scholar 

  20. Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and non-protein sulfhydryl groups in tissue with Ellman`s reagent. Ana Bioch 25:192–205

    Article  CAS  Google Scholar 

  21. Takamura Y, Fatman N, Kubo E, Singh DP (2006) Regulation of heavy subunit chain of γ-glutamylcysteine synthetase by tumor necrosis factor-α in lens epitherial cells: role of LEDGF/p75. Am J Physiol Cell Physiol 290:C554–C566

    Article  PubMed  CAS  Google Scholar 

  22. Versantvoort CHM, Broxterman HJ, Bagrij T, Scheper RJ, Twentyman P (1995) Regulation by glutathione of drug transport in multidrug-resistance-associated protein. Brit J Cancer 72:82–89

    PubMed  CAS  Google Scholar 

  23. Yao K-S, Godwin AK, Johnson SW, Ozols RF, O’Dwyer PJ, Hamilton TC (1995) Evidence for altered regulation of γ-glutamylcysteine synthetase gene expression among cisplatin-sensitive and cisplatin-resistant human ovarian cancer cell lines. Cancer Res 55:4367–4374

    PubMed  CAS  Google Scholar 

  24. Zhi H, Zhang J, Hu G, Lu J, Wang X, Zhou C, Wu M, Liu Z (2003) The deregulation of arachidonic acid metabolism-related genes in human esophageal squamous cell carcinoma. Int J Cancer 106:327–333

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by Grant-in-Aid for Scientific Research C (2) from the Ministry of Education, Culture, Sports, Science, and Technology (10670147, 13670848, and 50173448).

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Authors and Affiliations

  1. Department of Pediatrics, Nippon Medical School, Chiba Hokusoh Hospital, 1715 Kamakari, Inba-mura, Inba-gun, Chiba, 270-1894, Japan

    Takeshi Asano, Arisa Tsutsuda-Asano & Yoshitaka Fukunaga

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  1. Takeshi Asano
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  2. Arisa Tsutsuda-Asano
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  3. Yoshitaka Fukunaga
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Correspondence to Takeshi Asano.

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Asano, T., Tsutsuda-Asano, A. & Fukunaga, Y. Indomethacin overcomes doxorubicin resistance by decreasing intracellular content of glutathione and its conjugates with decreasing expression of γ-glutamylcysteine synthetase via promoter activity in doxorubicin-resistant leukemia cells. Cancer Chemother Pharmacol 64, 715–721 (2009). https://doi.org/10.1007/s00280-008-0920-6

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  • DOI: https://doi.org/10.1007/s00280-008-0920-6

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