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Combined Use of Anticancer Drugs and an Inhibitor of Multiple Drug Resistance-Associated Protein-1 Increases Sensitivity and Decreases Survival of Glioblastoma Multiforme Cells In Vitro

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Abstract

Glioblastoma multiforme (GBM) is a brain tumour characterised by a remarkably high chemoresistance and infiltrating capability. To date, chemotherapy with temozolomide has contributed only poorly to improved survival rates in patients. One of the most important mechanisms of chemoresistance comes about through the activity of certain proteins from the ATP-binding cassette superfamily that extrudes antitumour drugs, or their metabolites, from cells. We identify an increased expression of the multiple drug resistance-associated protein 1 (Mrp1) in glioblastoma multiforme biopsies and in T98G and G44 cell lines. The activity of this transporter was also confirmed by measuring the extrusion of the fluorescent substrate CFDA. The sensitivity of GBM cells was low upon exposure to temozolomide, vincristine and etoposide, with decreases in cell viability of below 20% seen at therapeutic concentrations of these drugs. However, combined exposure to vincristine or etoposide with an inhibitor of Mrp1 efficiently decreased cell viability by up to 80%. We conclude that chemosensitization of cells with inhibitors of Mrp1 activity might be an efficient tool for the treatment of human GBM.

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Acknowledgments

This work was supported by grants from FONDECYT-Chile 11080226, DID UACH SB2007-68 and PIA ANILLO ACT73 from CONICYT Chile.

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Authors and Affiliations

  1. Instituto de Bioquímica, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja s/n, P.O. box 567, Valdivia, Chile

    Lilia Peigñan, Wallys Garrido, Juan Guillermo Cárcamo, Rody San Martín & Claudia Quezada

  2. Servicio de Neurocirugía, Instituto de Neurocirugía Dr. Asenjo, Santiago, Chile

    Rodrigo Segura, Rómulo Melo & David Rojas

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  1. Lilia Peigñan
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  2. Wallys Garrido
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Correspondence to Claudia Quezada.

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Peigñan, L., Garrido, W., Segura, R. et al. Combined Use of Anticancer Drugs and an Inhibitor of Multiple Drug Resistance-Associated Protein-1 Increases Sensitivity and Decreases Survival of Glioblastoma Multiforme Cells In Vitro. Neurochem Res 36, 1397–1406 (2011). https://doi.org/10.1007/s11064-011-0464-8

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