FK506 Attenuates the MRP1-Mediated Chemoresistant Phenotype in Glioblastoma Stem-Like Cells
AbstractPoor 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
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Torres, Á.; Arriagada, V.; Erices, J.I.; Toro, M.D.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.
Torres Á, Arriagada V, Erices JI, Toro MDÁ, Rocha JD, Niechi I, Carrasco C, Oyarzún C, Quezada C. FK506 Attenuates the MRP1-Mediated Chemoresistant Phenotype in Glioblastoma Stem-Like Cells. International Journal of Molecular Sciences. 2018; 19(9):2697.Chicago/Turabian Style
Torres, Ángelo; Arriagada, Valentina; Erices, José I.; Toro, María D.Á.; Rocha, José D.; Niechi, Ignacio; Carrasco, Cristian; Oyarzún, Carlos; Quezada, Claudia. 2018. "FK506 Attenuates the MRP1-Mediated Chemoresistant Phenotype in Glioblastoma Stem-Like Cells." Int. J. Mol. Sci. 19, no. 9: 2697.
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