Journal of Neuro-Oncology

, Volume 110, Issue 1, pp 129–135 | Cite as

Multidrug resistance proteins expression in glioma patients with epilepsy

  • Chiara Calatozzolo
  • Bianca Pollo
  • Andrea Botturi
  • Loredana Dinapoli
  • Mariantonia Carosi
  • Andrea SalmaggiEmail author
  • Marta Maschio
Clinical Study - Patient Study


Epilepsy occurs in glioma, especially in low-grade glioma (LGG), but also in glioblastoma (GBM). In about 20 % of patients pharmacological treatment with anti-epileptic drugs (AEDs) fails. Refractory epilepsy is a multifactorial phenomenon not yet completely understood. The multidrug resistance phenotype was initially associated to P-glycoprotein (Pgp), an ATP-dependent transporter belonging to the same superfamily of multidrug resistance-associated proteins (MRPs). Glutathione-S-transferase-π (GST-π) is also involved in refractory epilepsy. In the present work we investigated the expression of Pgp, MRP1, MRP3 and GST-π in surgical specimens obtained from 35 patients with glioma and epilepsy. We observed MRP1 expression in tumor and endothelial cells (EC), MRP3 and Pgp expression mainly in ECs and GST-π predominantly in tumor cells (TC). MRP1 and MRP3 were more expressed in high grade glioma (HGG) than in LGG. In 6 cases we could compare tumor and periphery detecting the same MRP1 and Pgp expression, while MRP3 was mainly expressed in the tumor. We observed a trend of a better outcome in seizure control associated with a lower expression of MRP1 and MRP3. MRP3 was statistically more expressed in TCs of HGG than LGG (p = 0.0401) and more expressed in tumor than in periphery, in agreement with recent works that identify MRP3 as a potential target in GBM. Moreover, MRP3 was investigated in association with refractory epilepsy for the first time in our study and it was less expressed in patients with complete response to AEDs (p = 0.0550). Our preliminary data show an association between multidrug resistance transporters and refractory epilepsy in glioma.


Multidrug resistance Epilepsy Glioma Pgp MRP1 MRP3 GST-π 



We thank Dr. E. Ciusani, Dr. C. Vasco and Dr. G. Bedini of Laboratory of Clinical Pathology and Medical Genetics, Fondazione IRCCS Istituto Neurologico “C. Besta”, for their helpful collaboration in western blot analysis.

Conflicts of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Vecht CJ, Wilms EB (2010) Seizures in low- and high-grade gliomas: current management and future outlook. Expert Rev Anticancer Ther 10(5):663–669. doi: 10.1586/era.10.48 PubMedCrossRefGoogle Scholar
  2. 2.
    Marchi N, Gonzalez-Martinez J, Nguyen MT, Granata T, Janigro D (2010) Transporters in drug-refractory epilepsy: clinical significance. Clin Pharmacol Ther 87(1):13–15. doi: 10.1038/clpt.2009.225 PubMedCrossRefGoogle Scholar
  3. 3.
    Cascorbi I (2010) ABC transporters in drug-refractory epilepsy: limited clinical significance of pharmacogenetics? Clin Pharmacol Ther 87(1):15–18. doi: 10.1038/clpt.2009.237 PubMedCrossRefGoogle Scholar
  4. 4.
    Keppler D (2011) Multidrug resistance proteins (MRPs, ABCCs): importance for pathophysiology and drug therapy. Handb Exp Pharmacol 201:299–323. doi: 10.1007/978-3-642-14541-4_8 PubMedCrossRefGoogle Scholar
  5. 5.
    Sisodiya SM, Lin WR, Harding BN, Squier MV, Thom M (2002) Drug resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy. Brain 125(Pt 1):22–31. doi: 10.1093/brain/awf002 PubMedCrossRefGoogle Scholar
  6. 6.
    Shang W, Liu WH, Zhao XH, Sun QJ, Bi JZ, Chi ZF (2008) Expressions of glutathione S-transferase alpha, mu, and pi in brains of medically intractable epileptic patients. BMC Neurosci 18(9):67. doi: 10.1186/1471-2202-9-67 CrossRefGoogle Scholar
  7. 7.
    Calatozzolo C, Gelati M, Ciusani E, Sciacca FL, Pollo B, Cajola L, Marras C, Silvani A, Vitellaro-Zuccarello L, Croci D, Boiardi A, Salmaggi A (2005) Expression of drug resistance proteins Pgp, MRP1, MRP3, MRP5 and GST-pi in human glioma. J Neurooncol 74(2):113–121. doi: 10.1007/s11060-004-6152-7 PubMedCrossRefGoogle Scholar
  8. 8.
    Kuo MT (2009) Redox regulation of multidrug resistance in cancer chemotherapy: molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal 11(1):99–133. doi: 10.1089/ars.2008.2095 PubMedCrossRefGoogle Scholar
  9. 9.
    Lazarowski A, Czornyj L, Lubienieki F, Girardi E, Vazquez S, D’Giano C (2007) ABC transporters during epilepsy and mechanisms underlying multidrug resistance in refractory epilepsy. Epilepsia 48(Suppl 5):140–149. doi: 10.1111/j.1528-1167.2007.01302.x PubMedCrossRefGoogle Scholar
  10. 10.
    Kuan CT, Wakiya K, Herndon JE II, Lipp ES, Pegram CN, Riggins GJ, Rasheed A, Szafranski SE, McLendon RE, Wikstrand CJ, Bigner DD (2010) MRP3: a molecular target for human glioblastoma multiforme immunotherapy. BMC Cancer 10:468. doi: 10.1186/1471-2407-10-468 PubMedCrossRefGoogle Scholar
  11. 11.
    van Breemen MS, Wilms EB, Vecht CJ (2007) Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management. Lancet Neurol 6(5):421–430. doi: 10.1016/S1474-4422(07)70103-5 PubMedCrossRefGoogle Scholar
  12. 12.
    Kargiotis O, Markoula S (2011) Kyritsis AP epilepsy in the cancer patient. Cancer Chemother Pharmacol 67(3):489–501. doi: 10.1007/s00280-011-1569-0 PubMedCrossRefGoogle Scholar
  13. 13.
    Rosati A, Marconi S, Pollo B, Tomassini A, Lovato L, Maderna E, Maier K, Schwartz A, Rizzuto N, Padovani A, Bonetti B (2009) Epilepsy in glioblastoma multiforme: correlation with glutamine synthetase levels. J Neurooncol 93(3):319–324. doi: 10.1007/s11060-008-9794-z PubMedCrossRefGoogle Scholar
  14. 14.
    Liigant A, Haldre S, Oun A, Linnamägi U, Saar A, Asser T, Kaasik AE (2001) Seizure disorders in patients with brain tumors. Eur Neurol 45(1):46–51. doi: 10.1159/000052089 PubMedCrossRefGoogle Scholar
  15. 15.
    Englot DJ, Berger MS, Barbaro NM, Chang EF (2011) Predictors of seizure freedom after resection of supratentorial low-grade gliomas. A review. J Neurosurg 115(2):240–244. doi: 10.3171/2011.3.JNS1153 PubMedCrossRefGoogle Scholar
  16. 16.
    Baltes S, Gastens AM, Fedrowitz M, Potschka H, Kaever V, Löscher W (2007) Differences in the transport of the antiepileptic drugs phenytoin, levetiracetam and carbamazepine by human and mouse P-glycoprotein. Neuropharmacology 52(2):333–346. doi: 10.1016/j.neuropharm.2006.07.038 PubMedCrossRefGoogle Scholar
  17. 17.
    Summers MA, Moore JL, McAuley JW (2004) Use of verapamil as a potential P-glycoprotein inhibitor in a patient with refractory epilepsy. Ann Pharmacother 38(10):1631–1634. doi: 10.1345/aph.1E068 PubMedCrossRefGoogle Scholar
  18. 18.
    Iannetti P, Spalice A, Parisi P (2005) Calcium-channel blocker verapamil administration in prolonged and refractory status epilepticus. Epilepsia 46(6):967–969. doi: 10.1111/j.1528-1167.2005.59204.x PubMedCrossRefGoogle Scholar
  19. 19.
    Löscher W (2007) Drug transporters in the epileptic brain. Epilepsia 48(Suppl 1):8–13. doi: 10.1111/j.1528-1167.2007.00993.x PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Chiara Calatozzolo
    • 1
  • Bianca Pollo
    • 1
  • Andrea Botturi
    • 2
  • Loredana Dinapoli
    • 3
  • Mariantonia Carosi
    • 4
  • Andrea Salmaggi
    • 2
    Email author
  • Marta Maschio
    • 3
  1. 1.Department of NeuropathologyFondazione IRCCS Istituto Neurologico “C. Besta”MilanItaly
  2. 2.Department of Neuro-oncologyFondazione IRCCS Istituto Neurologico “C. Besta”MilanItaly
  3. 3.Center for Brain Tumor-related EpilepsyIstituto Nazionale Tumori “Regina Elena”RomeItaly
  4. 4.Department of PathologyIstituto Nazionale Tumori “Regina Elena”RomeItaly

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