Skip to main content
SpringerLink
Log in

Indomethacin overcomes doxorubicin resistance with inhibiting multi-drug resistance protein 1 (MRP1)

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

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 10 μM increased the cytotoxicity of doxorubicin, as well as vincristine in K562/ADR. Both multi-drug resistant protein1 (MRP1) and P-glycoprotein were overexpressed in K562/ADR cells when compared with K562 parent cells (K562/P). Expression of MRP1 mRNA and protein, but not P-glycoprotein, was significantly decreased in K562/ADR cells after indomethacin treatment. Indomethacin treatment increased 5(6)-carboxyfluorescein diacetate (CFDA) efflux, as well as decreased accumulation in K562/ADR cells. The activity of the MRP1 promoter decreased after indomethacin treatment in Hela cells. These data strongly suggest that the cyclooxygenase inhibitor, indomethacin, increased the cytotoxicity of doxorubicin with decreasing expression of MRP1 through inhibition of MRP1 promoter activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Asano T, An T, Mayes J, Zwelling LA, Kleinerman ES (1996) Transfection of human topoisomerase IIα gene increase in sensitivity followed by down-regulation of the endogenous gene. Biochem J 319:307–313

    PubMed  CAS  Google Scholar 

  2. 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 

  3. 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 Tech 7:1096–1103

    CAS  Google Scholar 

  4. Draper MP, Martell RL, Levy SB (1997) Indomethacin-mediated reversal of multidrug resistance and drug efflux in human and murine cell line overexpressing MRP, but not P-glycoprotein. Br J Cancer 75:810–815

    PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  7. 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 

  8. Kurz EU, Cole SP, Deeley RG (2001) Identification of DNA-protein interactions in 5′ flanking and 5′ untranslated regions of the human multidrug resistance protein (MRP1) gene evaluation of a putative antioxidant response element/AP-1 binding site. Biochem Biophys Res Commun 285:981–990

    Article  PubMed  CAS  Google Scholar 

  9. Legrand O, Simonin G, Beauchamp-Nicoud A, Zittoun R, Marie J-P (1999) Simultaneous activity of MRP1 and Pgp is correlated with in vitro resistance to daunorubicin and with in vivo resistance in adult acute myeloid leukemia. Blood 94:1045–1056

    Google Scholar 

  10. Mahon F-X, Belloc F, Legarde V, Chollet C, Moreau-Gaudy F, Reiffers J, Goldman JM, Melo JV (2003) MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood 101:2368–2373

    Article  PubMed  CAS  Google Scholar 

  11. Meaden ER, Hoggard PG, Khoo SH, Back DJ (2002) Determination of P-gp and MRP1 expression and function in peripheral blood mononuclear cells in vivo. J Immunol Method 262:159–165

    Article  CAS  Google Scholar 

  12. Payen L, Courtois A, Campion J-P, Guillouzo A, Fardel O (2000) Characterization and inhibition by a wide range of xenobiotics of organic anion excretion by primary human hepatocytes. Biochem Pharmacol 60:1967–1975

    Article  PubMed  CAS  Google Scholar 

  13. 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 

  14. 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 

  15. Zaman GJR, Flens MJ, van Leusden MR, de Haas M, Muller HS, Lankelma J, Pinedo HM, Scheper RJ, Baas F, Broxterman HJ, Borst P (1994) The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump. Proc Natl Acad Sci USA 91:8822–8826

    Article  PubMed  CAS  Google Scholar 

  16. 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 

  17. Zhu Q, Center MS (1994) Cloning and sequence analysis of the promoter region of the MRP gene of HL60 cells isolated for resistance to adriamycin. Cancer Res 54:4488–4492

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

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

Author information

Authors and Affiliations

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

    Seita Matsunaga, Takeshi Asano, Arisa Tsutsuda-Asano & Yoshitaka Fukunaga

Authors
  1. Seita Matsunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takeshi Asano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arisa Tsutsuda-Asano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshitaka Fukunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takeshi Asano.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Matsunaga, S., Asano, T., Tsutsuda-Asano, A. et al. Indomethacin overcomes doxorubicin resistance with inhibiting multi-drug resistance protein 1 (MRP1). Cancer Chemother Pharmacol 58, 348–353 (2006). https://doi.org/10.1007/s00280-005-0162-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-005-0162-9

Keywords

Search

Navigation