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Inhibition of Multidrug Resistance Protein I (MRP1) improves chemotherapy drug response in primary and recurrent glioblastoma multiforme

Tivnan, A. Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York House, St. Stephens Green, Dublin 2, Ireland; Zakaria, Z. Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York House, St. Stephens Green, Dublin 2, Ireland; O’Leary, C. Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York House, St. Stephens Green, Dublin 2, Ireland; Pokorny, J.L. Department of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, United States of America.; Sarkaria, J.N. Department of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, United States of America.; Kögel, D. Experimental Neurosurgery, Neuroscience Center, Frankfurt University Clinics, Theodor-Stern-Kai 7, D-60590, Frankfurt en Main, Germany; Prehn, J.H.M. Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York House, St. Stephens Green, Dublin 2, Ireland;


Glioblastoma multiforme (GBM) is a highly aggressive grade IV brain cancer with an extremely poor prognostic outcome despite intensive treatment regimes. GBM represent ~17% of all primary brain tumours diagnosed worldwide; and 60-75% of astrocytomas, increasing in frequency with age (1). The average five year survival is less than 3%, leading to the fact that GBM is the most lethal form of brain, or central nervous system (CNS), tumour. Despite surgical resection of GBM tumours, recurrence at distal sites is typically 6.9 months (2-4) and in instances where repeat resection is not a viable option, adjunct chemotherapy is ineffective at stopping tumour progression and, eventually, morbidity. All chemotherapeutic agents currently used; however, have no greater than 30-40% response rate and many fall into the range of 10-20%(5) with delivery across the blood brain barrier or chemoresistance contributing to the extremely poor patient outcomes despite treatment.
Increased expression of the multidrug resistance protein 1(MRP1) in high grade glioma, and it’s role in blood brain barrier active transport, renders this member of the ABC transporter family, a potential target for improving drug responses in this highly aggressive brain cancer. In this study we show that small molecule inhibitors of MRP1 had a significant effect on GBM cell drug responses to Temozolomide (150µM), Vincristine (100nM) and Etoposide (2µM). Pre-treatment with Reversan led to a significantly improved response in terms of Temozolomide, Vincristine and Etoposide-induced cell death, in both primary and recurrent GBM cell lines. The presence of MK571 led to an enhanced effect of Vincristine and Etoposide in reducing cell viability over a 72 hour period. MRP1 and MRP4 inhibition by MK571 did not have any effect on Temozolomide drug response in these cells. To ensure that the observed findings were MRP1 specific, an MRP1-targeting siRNA was used in three glioblastoma cell lines. Specific MRP1 inhibition led to a significant increase in Vincristine and Etoposide-induced cell death in all three cell lines assessed; (*p<0.05, ***p<0.001) relative to single chemotherapy-induced cell death. Notably, specific MRP1 inhibition did not have any effect on Temozolomide-induced cell death. The findings of this study have significant implications in terms of providing researchers an opportunity to improve currently used chemotherapeutics for the initial treatment of primary GBM, and improved treatment for recurrent GBM patients.
1. WHO, IARC. http://globocan.iarc.fr/
2. Stupp R, et al. The New England journal of medicine. 2005;352:987-96.
3. Stupp R, et al. The lancet oncology. 2009;10:459-66.
4. Stupp R, et al. Annals of oncology .2010;21 Suppl 5:v190-3.
5. Brada M, et al. Journal of clinical oncology 2010;28:4601-8.

Format: Oral communication

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