Modulation of Placental Breast Cancer Resistance Protein by HDAC1 in Mice: Implications for Optimization of Pharmacotherapy During Pregnancy

Negative Control ◽

Great Promise ◽

Cancer Resistance ◽

Gene Expressions ◽

Time Curve ◽

AbstractBreast cancer resistance protein (BCRP/ABCG2) is a critical drug efflux transporters by limiting drugs’ transplacental transfer rates. More investigations on the regulation of placental BCRP offer great promise for enabling pronounced progress in individualized and safe pharmacotherapy during pregnancy. Histone deacetylases (HDACs) play an important role in epigenetic regulation of placental genes. It was reported recently by us that HDAC1 was involved in placental BCRP regulation in vitro. The aim of this study was to further explore the effect of HDAC1 on placental BCRP expression and functionality in animals. Randomly assigned C57BL pregnant dams received intraperitoneal injections of a negative control siRNA or Hdac1 siRNA from embryonic day 7.5 (E7.5) to E15.5, respectively. At E16.5, glyburide (GLB), a probe for evaluating placental BCRP efflux functionality, was injected via the tail vein. Animals were sacrificed through cervical dislocation at various times (5–180 min) after drug administration. The maternal blood, placentas, and fetal-units were collected. GLB concentrations were determined by a validated high-performance liquid chromatography/mass spectrometry (HPLC-MS) assay. Real-time quantitative PCR (qRT-PCR), Western blot, and immunohistochemical (IHC) analysis were employed to identify mRNA/protein levels and localization of gene expressions, respectively. It was noted that Hdac1 inhibition significantly decreased placental Bcrp expression, with markedly increases of GLB concentrations and area under the concentration-time curve (AUC) in fetal-units. Particularly, the ratios of fetal-unit/maternal plasma GLB concentrations were also significantly elevated following Hdac1 repression. Taken together, these findings suggested that HDAC1 was involved in positive regulation of placental BCRP expression and functionality in vivo.

Quercetin Is a Flavonoid Breast Cancer Resistance Protein Inhibitor with an Impact on the Oral Pharmacokinetics of Sulfasalazine in Rats

Pharmaceutics ◽

10.3390/pharmaceutics12050397 ◽

2020 ◽

Vol 12 (5) ◽

pp. 397

Author(s):

Yoo-Kyung Song ◽

Jin-Ha Yoon ◽

Jong Kyu Woo ◽

Ju-Hee Kang ◽

Kyeong-Ryoon Lee ◽

...

Keyword(s):

Breast Cancer ◽

Fold Increase ◽

Inhibitory Effect ◽

Dependent Manner ◽

Cancer Resistance ◽

Concentration Dependent Manner ◽

The potential inhibitory effect of quercetin, a major plant flavonol, on breast cancer resistance protein (BCRP) activity was investigated in this study. The presence of quercetin significantly increased the cellular accumulation and associated cytotoxicity of the BCRP substrate mitoxantrone in human cervical cancer cells (HeLa cells) in a concentration-dependent manner. The transcellular efflux of prazosin, a stereotypical BCRP substrate, was also significantly reduced in the presence of quercetin in a bidirectional transport assay using human BCRP-overexpressing cells; further kinetic analysis revealed IC50 and Ki values of 4.22 and 3.91 μM, respectively. Moreover, pretreatment with 10 mg/kg quercetin in rats led to a 1.8-fold and 1.5-fold increase in the AUC8h (i.e., 44.5 ± 11.8 min∙μg/mL vs. 25.7 ± 9.98 min∙μg/mL, p < 0.05) and Cmax (i.e., 179 ± 23.0 ng/mL vs. 122 ± 23.2 ng/mL, p < 0.05) of orally administered sulfasalazine, respectively. Collectively, these results provide evidence that quercetin acts as an in vivo as well as in vitro inhibitor of BCRP. Considering the high dietary intake of quercetin as well as its consumption as a dietary supplement, issuing a caution regarding its food–drug interactions should be considered.

In Vitro and In Vivo Evidence for the Importance of Breast Cancer Resistance Protein Transporters (BCRP/MXR/ABCP/ABCG2)

Handbook of Experimental Pharmacology - Drug Transporters ◽

10.1007/978-3-642-14541-4_9 ◽

2010 ◽

pp. 325-371 ◽

Cited By ~ 54

Author(s):

Henriette E. Meyer zu Schwabedissen ◽

Heyo K. Kroemer

Keyword(s):

Breast Cancer ◽

Cancer Resistance ◽

Resistance Protein ◽

Protein Transporters

Improved In Vitro-In Vivo Correlation by Using the Unbound-Fraction-Adjusted IC50 for Breast Cancer Resistance Protein Inhibition

Pharmaceutical Research ◽

10.1007/s11095-020-02954-1 ◽

2020 ◽

Vol 37 (12) ◽

Author(s):

Shunji Imai ◽

Toshiki Arai ◽

Tetsuhiro Yamada ◽

Makoto Niwa

Keyword(s):

Breast Cancer ◽

Cancer Resistance ◽

Unbound Fraction ◽

Protein Inhibition ◽

Relevance of Breast Cancer Resistance Protein to Pharmacokinetics of Florfenicol in Chickens: A Perspective from In Vivo and In Vitro Studies

International Journal of Molecular Sciences ◽

10.3390/ijms19103165 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3165 ◽

Cited By ~ 2

Author(s):

Yang Liu ◽

Li Guo ◽

Mire Zloh ◽

Yujuan Zhang ◽

Jinhu Huang ◽

...

Keyword(s):

Breast Cancer ◽

Mdck Cells ◽

Binding Pocket ◽

Chicken Breast ◽

Pharmacokinetic Studies ◽

Cancer Resistance ◽

Florfenicol (FFC) is a valuable synthetic fluorinated derivative of thiamphenicol widely used to treat infectious diseases in food animals. The aims of the study were to investigate whether FFC is a substrate for the breast cancer resistance protein (BCRP) and whether the transporter influences oral availability of FFC. In vitro transport assays using MDCK-chAbcg2 cells were conducted to assess chicken BCRP-mediated transport of FFC, while in vivo pharmacokinetic experiments with single or combined BCRP inhibitor gefitinib were employed to study the role of BCRP in oral FFC disposition. According to U.S. Food and Drug Administration (FDA) criteria, FFC was found to be a potential BCRP substrate due to the net efflux ratio being over 2.0 (2.37) in MDCK cells stably transfected with chicken BCRP and the efflux completely reversed by a BCRP inhibitor (Gefitinib). The molecular docking results indicated that florfenicol can form favorable interactions with the binding pocket of homology modeled chicken BCRP. Pharmacokinetic studies of FFC in different aged broilers with different expression levels of BCRP showed that higher BCRP expression would cause a lower Area Under Curve (AUC) and a higher clearance of FFC. In addition, more extensive absorption of florfenicol after the co-administration with gefitinib (a BCRP inhibitor) was observed. The overall results demonstrated that florfenicol is a substrate of the chicken breast cancer resistant protein which in turn affects its pharmacokinetic behavior.

EFFECTS OF DIHYDROPYRIDINES AND PYRIDINES ON MULTIDRUG RESISTANCE MEDIATED BY BREAST CANCER RESISTANCE PROTEIN: IN VITRO AND IN VIVO STUDIES

Drug Metabolism and Disposition ◽

10.1124/dmd.104.003558 ◽

2005 ◽

Vol 33 (8) ◽

pp. 1220-1228 ◽

Cited By ~ 44

Author(s):

Xiao-fei Zhou ◽

Xinning Yang ◽

Qi Wang ◽

Robert A. Coburn ◽

Marilyn E. Morris

Keyword(s):

Breast Cancer ◽

Multidrug Resistance ◽

In Vivo Studies ◽

Cancer Resistance ◽

Bisphenol A Inhibits the Transporter Function of the Blood-Brain Barrier by Directly Interacting with the ABC Transporter Breast Cancer Resistance Protein (BCRP)

International Journal of Molecular Sciences ◽

10.3390/ijms22115534 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5534

Author(s):

Elin Engdahl ◽

Maarten van Schijndel ◽

Dimitrios Voulgaris ◽

Michela Di Criscio ◽

Kerry Ramsbottom ◽

...

Keyword(s):

Breast Cancer ◽

Bisphenol A ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Production Volume ◽

Cancer Resistance ◽

Blood Brain ◽

The breast cancer resistance protein (BCRP) is an important efflux transporter in the blood-brain barrier (BBB), protecting the brain from a wide range of substances. In this study, we investigated if BCRP function is affected by bisphenol A (BPA), a high production volume chemical used in common consumer products, as well as by bisphenol F (BPF) and bisphenol S (BPS), which are used to substitute BPA. We employed a transwell-based in vitro cell model of iPSC-derived brain microvascular endothelial cells, where BCRP function was assessed by measuring the intracellular accumulation of its substrate Hoechst 33342. Additionally, we used in silico modelling to predict if the bisphenols could directly interact with BCRP. Our results showed that BPA significantly inhibits the transport function of BCRP. Additionally, BPA was predicted to bind to the cavity that is targeted by known BCRP inhibitors. Taken together, our findings demonstrate that BPA inhibits BCRP function in vitro, probably by direct interaction with the transporter. This effect might contribute to BPA’s known impact on neurodevelopment.

P-Glycoprotein and Breast Cancer Resistance Protein Restrict Apical-to-Basolateral Permeability of Human Brain Endothelium to Amyloid-β

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.42 ◽

2009 ◽

Vol 29 (6) ◽

pp. 1079-1083 ◽

Cited By ~ 73

Author(s):

Leon M Tai ◽

A Jane Loughlin ◽

David K Male ◽

Ignacio A Romero

Keyword(s):

Breast Cancer ◽

Human Brain ◽

Amyloid Β ◽

Cancer Resistance ◽

Glycoprotein P ◽

P Glycoprotein ◽

Resistance Protein ◽

The Brain

The clearance of amyloid beta (Aβ) from the brain represents a novel therapeutic target for Alzheimer's disease. Conflicting data exist regarding the contribution of adenosine triphosphatebinding cassette transporters to the clearance of Aβ through the blood-brain barrier. Therefore, we investigated whether Aβ could be a substrate for P-glycoprotein (P-gp) and/or for breast cancer resistance protein (BCRP) using a human brain endothelial cell line, hCMEC/D3. Inhibition of P-gp and BCRP increased apical-to-basolateral, but not basolateral-to-apical, permeability of hCMEC/D3 cells to 125l Aβ 1–40. Our in vitro data suggest that P-gp and BCRP might act to prevent the blood-borne Aβ 1–40 from entering the brain.