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Int. J. Mol. Sci. 2018, 19(9), 2697; https://doi.org/10.3390/ijms19092697

FK506 Attenuates the MRP1-Mediated Chemoresistant Phenotype in Glioblastoma Stem-Like Cells

1
Laboratorio de Patología Molecular, Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile
2
Departamento de Patología del Hospital Base de Valdivia (HBV), Valdivia 5090000, Chile
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 1 August 2018 / Revised: 25 August 2018 / Accepted: 29 August 2018 / Published: 11 September 2018
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Abstract

Poor response to current treatments for glioblastoma has been attributed to the presence of glioblastoma stem-like cells (GSCs). GSCs are able to expel antitumor drugs to the extracellular medium using the multidrug resistance-associated protein 1 (MRP1) transporter. Tacrolimus (FK506) has been identified as an MRP1 regulator in differentiated glioblastoma (GBM) cells (non-GSCs); however, the effect of FK506 on GSCs is currently unknown. The objective of the following research is to evaluate the effect of FK506 on the MRP1-related chemo-resistant phenotype of GSCs. For this, U87MG and C6 glioma cell lines were used to generate non-GSCs and GSCs. mRNA and MRP1-positive cells were evaluated by RT-qPCR and flow cytometry, respectively. A Carboxyfluorescein Diacetate (CFDA)-retention assay was performed to evaluate the MRP1 activity. Apoptosis and MTT assays were employed to evaluate the cytotoxic effects of FK506 plus Vincristine (MRP1 substrate). GSC-derived subcutaneous tumors were generated to evaluate the in vivo effect of FK506/Vincristine treatment. No differences in transcript levels and positive cells for MRP1 were observed in FK506-treated cells. Lesser cell viability, increased apoptosis, and CFDA-retention in the FK506/Vincristine-treated cells were observed. In vivo, the FK506/Vincristine treatment decreased the tumor size as well as ki67, Glial Fibrillary Acidic Protein (GFAP), and nestin expression. We conclude that FK506 confers a chemo-sensitive phenotype to MRP1-drug substrate in GSCs. View Full-Text
Keywords: ATP-binding cassette transporter; glioblastoma stem-like cells; multiple drug resistance; multidrug resistance-associated protein 1; tacrolimus ATP-binding cassette transporter; glioblastoma stem-like cells; multiple drug resistance; multidrug resistance-associated protein 1; tacrolimus
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Torres, Á.; Arriagada, V.; Erices, J.I.; Toro, M.Á.; Rocha, J.D.; Niechi, I.; Carrasco, C.; Oyarzún, C.; Quezada, C. FK506 Attenuates the MRP1-Mediated Chemoresistant Phenotype in Glioblastoma Stem-Like Cells. Int. J. Mol. Sci. 2018, 19, 2697.

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