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Journal of Neuro-Oncology

, Volume 57, Issue 1, pp 27–36 | Cite as

Expression and Functional Activity of the ABC-transporter Proteins P-glycoprotein and Multidrug-resistance Protein 1 in Human Brain Tumor Cells and Astrocytes

  • Sabine Spiegl-Kreinecker
  • Johanna Buchroithner
  • Leonilla Elbling
  • Elisabeth Steiner
  • Gabriele Wurm
  • Angelika Bodenteich
  • Johannes Fischer
  • Michael Micksche
  • Walter Berger
Article

Abstract

The poor prognosis of glioma patients is partly based on the minor success obtained from chemotherapeutic treatments. Resistance mechanisms at the tumor cell level may be, in addition to the blood–brain barrier, involved in the intrinsic chemo-insensitivity of brain tumors. We investigated the expression of the drug-transporter proteins P-glycoprotein (P-gp) and multidrug-resistance protein 1 (MRP1) in cell lines (N=24) and primary cell cultures (N=36) from neuroectodermal tumors, as well as in brain tumor extracts (N=18) and normal human astrocytes (N=1). We found that a considerable expression of P-gp was relatively rare in glioma cells, in contrast to MRP1, which was constitutively overexpressed in cells derived from astrocytomas as well as glioblastomas. Also, normal astrocytes cultured in vitro expressed high amounts of MRP1 but no detectable P-gp. Meningioma cells frequently co-expressed P-gp and MRP1, while, most of the neuroblastoma cell lines express higher P-gp but lower MRP1 levels as compared to the other tumor types. Both, a drug-exporting and a chemoprotective function of P-gp as well as MRP1 could be demonstrated in selected tumor cells by a significant upregulation of cellular 3H-daunomycin accumulation and daunomycin cytotoxicity via administration of transporter antagonists. Summing up, our data suggest that P-gp contributes to cellular resistance merely in a small subgroup of gliomas, but frequently in neuroblastomas and meningiomas. In contrast, MRP1 is demonstrated to play a constitutive role in the intrinsic chemoresistance of gliomas and their normal cell counterpart.

brain tumor glioma astrocyte multidrug-resistance multidrug-resistance protein 1 P-glycoprotein 

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References

  1. 1.
    Prados MD, Levin V: Biology and treatment of malignant glioma. Semin Oncol 27: 1-10, 2000Google Scholar
  2. 2.
    Azizi SA, Miyamoto C: Principles of treatment of malignant gliomas in adults: an overview. J Neurovirol 4: 204-216, 1998Google Scholar
  3. 3.
    Bart J, Groen HJ, Hendrikse NH, van-der-Graaf WT, Vaalburg W, de-Vries EG: The blood-brain barrier and oncology: new insights into function and modulation. Cancer Treat Rev 26: 449-462, 2000Google Scholar
  4. 4.
    Cordon-Cardo C, O'Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, Bertino JR: Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at 36 blood-brain barrier sites. Proc Natl Acad Sci USA 86: 695-698, 1989Google Scholar
  5. 5.
    Zhang Y, Han H, Elmquist WF, Miller DW: Expression of various multidrug resistance-associated protein (MRP) homologues in brain microvessel endothelial cells. Brain Res 876: 148-153, 2000Google Scholar
  6. 6.
    Yamashima T, Ohnishi T, Nakajima Y, Terasaki T, Tanaka M, Yamashita J, Sasaki T, Tsuji A: Uptake of drugs and expression of P-glycoprotein in the rat 9L glioma. Exp Brain Res 95: 41-50, 1993Google Scholar
  7. 7.
    Tan B, Piwnica-Worms D, Ratner L: Multidrug resistance transporters and modulation. Curr Opin Oncol 12: 450-458, 2000Google Scholar
  8. 8.
    Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, Stewart AJ, Kurz EU, Duncan AM, Deeley RG: Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 258: 1650-1654, 1992Google Scholar
  9. 9.
    Gottesman MM, Pastan I, Ambudkar SV: P-glycoprotein and multidrug resistance. Curr Opin Genet Dev 6: 610-617, 1996Google Scholar
  10. 10.
    Ashmore SM, Thomas DG, Darling JL: Does P-glycoprotein play a role in clinical resistance of malignant astrocytoma? Anticancer Drugs 10: 861-872, 1999Google Scholar
  11. 11.
    Bredel M: Anticancer drug resistance in primary human brain tumors. Brain Res Rev 35: 161-204, 2001Google Scholar
  12. 12.
    Abe T, Hasegawa S, Taniguchi K, Yokomizo A, Kuwano T, Ono M, Mori T, Hori S, Kohno K, Kuwano M: Possible involvement of multidrug-resistance-associated protein (MRP) gene expression in spontaneous drug resistance to vincristine, etoposide and adriamycin in human glioma cells. Int J Cancer 58: 860-864, 1994Google Scholar
  13. 13.
    Mohri M, Nitta H, Yamashita J: Expression of multidrug resistance-associated protein (MRP) in human gliomas. J Neuro-Oncol 49: 105-115, 2001Google Scholar
  14. 14.
    Berger W, Elbling L, Micksche M: Expression of the major vault proteinLRPin human non-small-cell lung cancer cells: activation by short-term exposure to antineoplastic drugs. Int J Cancer 88: 293-300, 2000Google Scholar
  15. 15.
    Berger W, Hauptmann E, Elbling L, Vetterlein M, Kokoschka EM, Micksche M: Possible role of the multidrug resistance-associated protein (MRP) in chemoresistance of human melanoma cells. Int J Cancer 71: 108-115, 1997Google Scholar
  16. 16.
    Tanaka Y, Abe Y, Tsugu A, Takamiya Y, Akatsuka A, Tsuruo T, Yamazaki H, Ueyama Y, Sato O, Tamaoki N, Nakamura M: Ultrastructural localization of P-glycoprotein on capillary endothelial cells in human gliomas. Virchows Arch 425: 133-138, 1994Google Scholar
  17. 17.
    von-Bossanyi P, Diete S, Dietzmann K, Warich-Kirches M, Kirches E: Immunohistochemical expression of P-glycoprotein and glutathione S-transferases in cerebral gliomas and response to chemotherapy. Acta Neuropathol (Berl) 94: 605-611, 1997Google Scholar
  18. 18.
    Demeule M, Shedid D, Beaulieu E, Del-Maestro RF, Moghrabi A, Ghosn PB, Moumdjian R, Berthelet F, Beliveau R: Expression of multidrug-resistance P-glycoprotein (MDR1) in human brain tumors. Int J Cancer 93: 62-66, 2001Google Scholar
  19. 19.
    Sawada T, Kato Y, Sakayori N, Takekawa Y, Kobayashi M: Expression of the multidrug-resistance P-glycoprotein (Pgp, MDR-1) by endothelial cells of the neovasculature in central nervous system tumors. Brain Tumor Pathol 16: 23-27, 1999Google Scholar
  20. 20.
    Toth K, Vaughan MM, Peress NS, Slocum HK, Rustum YM: MDR1 P-glycoprotein is expressed by endothelial cells of newly formed capillaries in human gliomas but is not expressed in the neovasculature of other primary tumors. Am J Pathol 149: 853-858, 1996Google Scholar
  21. 21.
    Demeule M, Labelle M, Regina A, Berthelet F, Beliveau R: Isolation of endothelial cells from brain, lung, and kidney: expression of the multidrug resistance P-glycoprotein isoforms. Biochem Biophys Res Commun 281: 827-834, 2001Google Scholar
  22. 22.
    Gomi A, Shinoda S, Masuzawa T, Ishikawa T, Kuo MT: Transient induction of the MRP/GS-X pump and gammaglutamylcysteine synthetase by 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea in human glioma cells. Cancer Res 57: 5292-5299, 1997Google Scholar
  23. 23.
    Abe T, Mori T, Wakabayashi Y, Nakagawa M, Cole SP, Koike K, Kuwano M, Hori S: Expression of multidrug resistance protein gene in patients with glioma after chemotherapy. J Neuro-Oncol 40: 11-18, 1998Google Scholar
  24. 24.
    Decleves X, Regina A, Laplanche JL, Roux F, Boval B, Launay JM, Scherrmann JM: Functional expression of P-glycoprotein and multidrug resistance-associated protein (Mrp1) in primary cultures of rat astrocytes. J Neurosci Res 60: 594-601, 2000Google Scholar
  25. 25.
    Golden PL, Pardridge WM: Brain microvascular P-glycoprotein and a revised model of multidrug resistance in brain. Cell Mol Neurobiol 20: 165-181, 2000Google Scholar
  26. 26.
    Hollo Z, Homolya L, Hegedus T, Sarkadi B: Transport properties of the multidrug resistance-associated protein (MRP) in human tumour cells. FEBS Lett 383: 99-104, 1996Google Scholar
  27. 27.
    Rieger L, Rieger J, Winter S, Streffer J, Esser P, Dichgans J, Meyermann R, Weller M: Evidence for a constitutive, verapamil-sensitive, non-P-glycoprotein multidrug resistance phenotype in malignant glioma that is unaltered by radiochemotherapy in vivo. Acta Neuropathol (Berl) 99: 555-562, 2000Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Sabine Spiegl-Kreinecker
    • 1
  • Johanna Buchroithner
    • 1
  • Leonilla Elbling
    • 2
  • Elisabeth Steiner
    • 2
  • Gabriele Wurm
    • 1
  • Angelika Bodenteich
    • 3
  • Johannes Fischer
    • 1
  • Michael Micksche
    • 2
  • Walter Berger
    • 3
  1. 1.Department of NeurosurgeryLandesnervenklinik Wagner-Jauregg HospitalLinzAustria
  2. 2.Vienna UniversityViennaAustria
  3. 3.Department of PathologyLandesnervenklinik Wagner-Jauregg HospitalLinzAustria

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