Regulation of Breast Cancer Resistant Protein by Peroxisome Proliferator-Activated Receptor α in Human Brain Microvessel Endothelial Cells

Hoque, Md. Tozammel; Robillard, Kevin R.; Bendayan, Reina

doi:10.1124/mol.111.076745

Cited by 49 publications

(41 citation statements)

References 42 publications

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“…BCRP has been reported to be modulated by a number of nuclear receptors including peroxisome proliferator-activated receptor α (PPARα) in human immortalised hCMEC/D3 cells (132,133), nuclear factor kB (NF-kB) in primary (134) and immortalised (hCMEC/D3) (135) brain endothelial cells, pregnane X receptor (PXR) and constitutive androstane receptor (CAR) (136,137), esteogen receptors in rodent brain capillaries (77) (138) and recently the aryl hydrocarbon receptor (AhR) (66, [139][140][141][142].…”

Section: Discussionmentioning

confidence: 99%

Phytoestrogens Modulate Breast Cancer Resistance Protein Expression and Function at the Blood-Cerebrospinal Fluid Barrier

Kaur

Badhan

2015

J Pharm Pharm Sci

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-PURPOSE: Breast cancer resistance protein (BCRP/ABCG2) is a drug efflux transporter expressed at the blood cerebrospinal fluid barrier (BCSFB), and influences distribution of drugs into the central nervous systems (CNS). Current inhibitors have failed clinically due to neurotoxicity. Novel approaches are needed to identify new modulators to enhance CNS delivery. This study examines 18 compounds (mainly phytoestrogens) as modulators of the expression/function of BCRP in an in vitro rat choroid plexus BCSFB model. METHODS: Modulators were initially subject to cytotoxicity (MTT) assessment to determine optimal non-toxic concentrations. Reverse-transcriptase PCR and confocal microscopy were used to identify the presence of BCRP in Z310 cells. Thereafter modulation of the intracellular accumulation of the fluorescent BCRP probe substrate Hoechst 33342 (H33342), changes in protein expression of BCRP (western blotting) and the functional activity of BCRP (membrane insert model) were assessed under modulator exposure. RESULTS: A 24 hour cytotoxicity assay (0.001 µM-1000 µM) demonstrated the majority of modulators possessed a cellular viability IC50 > 148 µM. Intracellular accumulation of H33342 was significantly increased in the presence of the known BCRP inhibitor Ko143 and, following a 24 hour pre-incubation, all modulators demonstrated statistically significant increases in H33342 accumulation (P < 0.001), when compared to control and Ko143. After a 24 hour pre-incubation with modulators alone, a 0.16-2.5 -fold change in BCRP expression was observed for test compounds. The functional consequences of this were confirmed in a permeable insert model of the BCSFB which demonstrated that 17-β-estradiol, naringin and silymarin (down-regulators) and baicalin (up-regulator) can modulate BCRP-mediated transport function at the BCSFB. CONCLUSION: We have successfully confirmed the gene and protein expression of BCRP in Z310 cells and demonstrated the potential for phytoestrogen modulators to influence the functionality of BCRP at the BCSFB and thereby potentially allowing manipulation of CNS drug disposition.

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Section: Discussionmentioning

confidence: 99%

Phytoestrogens Modulate Breast Cancer Resistance Protein Expression and Function at the Blood-Cerebrospinal Fluid Barrier

Kaur

Badhan

2015

J Pharm Pharm Sci

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“…3B). Recently, another isoform, PPARα, has also been shown to directly induce ABCG2 mRNA and protein expression through binding to the same conserved enhancer region of the ABCG2 gene in human brain microvessel endothelial cells (Hoque, Robillard, & Bendayan, 2012). In primary human hepatocytes, exposure to certain NR ligands resulted in enhanced ABCG2 mRNA expression, strongly suggesting the regulatory role of the PXR and CAR pathways ( Jigorel et al, 2006).…”

Section: P0305mentioning

confidence: 99%

Lipid Regulation of the ABCB1 and ABCG2 Multidrug Transporters

Hegedüs

Telbisz

Hegedüs

et al. 2015

Advances in Cancer Research

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“…The mouse Sertoli testicular (TM4) and Caco-2 cell lines were obtained from the American Tissue Culture Collection (Manassas, VA). These cells were cultured as described in our previous publications and those of others (24,26,27).…”

Section: Materials Raltegravir and [mentioning

confidence: 99%

“…In addition, raltegravir is reported to have low oral bioavailability in humans (20)(21)(22). Studies from our group and those of others have shown the functional expression of several ABC drug efflux transporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated proteins (MRPs), in blood-brain barrier, blood-testicular barrier, and blood-intestinal barrier models, which can collectively serve as a biochemical barrier to drug entry/distribution in these tissues (23)(24)(25)(26)(27). Raltegravir interactions with P-gp and BCRP transporters were recently investigated in a few studies; however, inconsistent results have been reported, depending on the methods used (28)(29)(30).…”

mentioning

confidence: 99%

Raltegravir Permeability across Blood-Tissue Barriers and the Potential Role of Drug Efflux Transporters

Hoque

Kis

Rosa

et al. 2015

Antimicrob Agents Chemother

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The objectives of this study were to investigate raltegravir transport across several blood-tissue barrier models and the potential interactions with drug efflux transporters. Raltegravir uptake, accumulation, and permeability were evaluated in vitro in (i) Pglycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance-associated protein 1 (MRP1), or MRP4-overexpressing MDA-MDR1 (P-gp), HEK-ABCG2, HeLa-MRP1, or HEK-MRP4 cells, respectively; (ii) cell culture systems of the human blood-brain (hCMEC/D3), mouse blood-testicular (TM4), and human blood-intestinal (Caco-2) barriers; and (iii) rat jejunum and ileum segments using an in situ single-pass intestinal perfusion model. Our data suggest that raltegravir is a substrate but not an inhibitor of the drug efflux transporters P-gp and BCRP. These transporters might play a role in the restriction of raltegravir permeability across the blood-brain, bloodtesticular, and blood-intestinal barriers, potentially contributing to its low tissue concentrations and/or low oral bioavailability observed in the clinic setting.

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Regulation of Breast Cancer Resistant Protein by Peroxisome Proliferator-Activated Receptor α in Human Brain Microvessel Endothelial Cells

Cited by 49 publications

References 42 publications

Phytoestrogens Modulate Breast Cancer Resistance Protein Expression and Function at the Blood-Cerebrospinal Fluid Barrier

Phytoestrogens Modulate Breast Cancer Resistance Protein Expression and Function at the Blood-Cerebrospinal Fluid Barrier

Lipid Regulation of the ABCB1 and ABCG2 Multidrug Transporters

Raltegravir Permeability across Blood-Tissue Barriers and the Potential Role of Drug Efflux Transporters

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