Phytochemical mediated-modulation of the expression and transporter function of breast cancer resistance protein at the blood-brain barrier:an in-vitro study

Kaur, Manjit and Badhan, Raj K.S. (2017). Phytochemical mediated-modulation of the expression and transporter function of breast cancer resistance protein at the blood-brain barrier:an in-vitro study. Brain Research, 1654 , pp. 9-23.

Abstract

Clinical translation of BCRP inhibitors have failed due to neurotoxicity and novel approaches are required to identify suitable modulators of BCRP to enhance CNS drug delivery. In this study we examine 18 compounds, primarily phytochemicals, as potential novel modulators of AhR-mediated regulation of BCRP expression and function in immortalised and primary porcine brain microvascular endothelial cells as a mechanism to enhance CNS drug delivery. The majority of modulators possessed a cellular viability IC50 > 100 µM in both cell systems. BCRP activity, when exposed to modulators for 1 hour, was diminished for most modulators through significant increases in H33342 accumulation at < 10 µM with 2,6,4-trimethoflavone increasing H33342 intracellular accumulation by 3.7–6.6 fold over 1–100 µM. Western blotting and qPCR identified two inducers of BCRP (quercetin and naringin) and two down-regulators (17-β-estradiol and curcumin) with associated changes in BCRP efflux transport function further confirmed in both cell lines. siRNA downregulation of AhR resulted in a 1.75 ± 0.08 fold change in BCRP expression, confirming the role of AhR in the regulation of BCRP. These findings establish the regulatory role AhR of in controlling BCRP expression at the BBB and confirm quercetin, naringin, 17-β-estradiol, and curcumin as novel inducers and down-regulators of BCRP gene, protein expression and functional transporter activity and hence potential novel target sites and candidates for enhancing CNS drug delivery.

Publication DOI: https://doi.org/10.1016/j.brainres.2016.10.020
Divisions: Life & Health Sciences > Pharmacy
Life & Health Sciences
Life & Health Sciences > Chronic and Communicable Conditions
Life & Health Sciences > Applied Health Research Group
Additional Information: © 2016, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Uncontrolled Keywords: breast cancer resistance protein,central nervous system,brain,flavonoid,aryl hydrocarbon receptor,Neuroscience(all),Molecular Biology,Developmental Biology,Clinical Neurology
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
Published Date: 2017-01-01
Authors: Kaur, Manjit
Badhan, Raj K.S. ( 0000-0002-0904-9324)

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