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Mechanism of drug extrusion by brain endothelial cells via lysosomal drug trapping and disposal by neutrophils
The blood–brain barrier protects the brain against a variety of potentially toxic compounds. Barrier function results from tight junctions between brain capillary endothelial cells and high expression of active efflux transporters, including P-glycoprotein (Pgp), at the apical membrane of these cell...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187170/ https://www.ncbi.nlm.nih.gov/pubmed/30254169 http://dx.doi.org/10.1073/pnas.1719642115 |
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author | Noack, Andreas Gericke, Birthe von Köckritz-Blickwede, Maren Menze, Arne Noack, Sandra Gerhauser, Ingo Osten, Felix Naim, Hassan Y. Löscher, Wolfgang |
author_facet | Noack, Andreas Gericke, Birthe von Köckritz-Blickwede, Maren Menze, Arne Noack, Sandra Gerhauser, Ingo Osten, Felix Naim, Hassan Y. Löscher, Wolfgang |
author_sort | Noack, Andreas |
collection | PubMed |
description | The blood–brain barrier protects the brain against a variety of potentially toxic compounds. Barrier function results from tight junctions between brain capillary endothelial cells and high expression of active efflux transporters, including P-glycoprotein (Pgp), at the apical membrane of these cells. In addition to actively transporting drugs out of the cell, Pgp mediates lysosomal sequestration of chemotherapeutic drugs in cancer cells, thus contributing to drug resistance. Here, we describe that lysosomal sequestration of Pgp substrates, including doxorubicin, also occurs in human and porcine brain endothelial cells that form the blood–brain barrier. This is followed by shedding of drug-sequestering vesicular structures, which stay attached to the apical side of the plasma membrane and form aggregates (“barrier bodies”) that ultimately undergo phagocytosis by neutrophils, thus constituting an as-yet-undescribed mechanism of drug disposal. These findings introduce a mechanism that might contribute to brain protection against potentially toxic xenobiotics, including therapeutically important chemotherapeutic drugs. |
format | Online Article Text |
id | pubmed-6187170 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-61871702018-10-15 Mechanism of drug extrusion by brain endothelial cells via lysosomal drug trapping and disposal by neutrophils Noack, Andreas Gericke, Birthe von Köckritz-Blickwede, Maren Menze, Arne Noack, Sandra Gerhauser, Ingo Osten, Felix Naim, Hassan Y. Löscher, Wolfgang Proc Natl Acad Sci U S A PNAS Plus The blood–brain barrier protects the brain against a variety of potentially toxic compounds. Barrier function results from tight junctions between brain capillary endothelial cells and high expression of active efflux transporters, including P-glycoprotein (Pgp), at the apical membrane of these cells. In addition to actively transporting drugs out of the cell, Pgp mediates lysosomal sequestration of chemotherapeutic drugs in cancer cells, thus contributing to drug resistance. Here, we describe that lysosomal sequestration of Pgp substrates, including doxorubicin, also occurs in human and porcine brain endothelial cells that form the blood–brain barrier. This is followed by shedding of drug-sequestering vesicular structures, which stay attached to the apical side of the plasma membrane and form aggregates (“barrier bodies”) that ultimately undergo phagocytosis by neutrophils, thus constituting an as-yet-undescribed mechanism of drug disposal. These findings introduce a mechanism that might contribute to brain protection against potentially toxic xenobiotics, including therapeutically important chemotherapeutic drugs. National Academy of Sciences 2018-10-09 2018-09-25 /pmc/articles/PMC6187170/ /pubmed/30254169 http://dx.doi.org/10.1073/pnas.1719642115 Text en Copyright © 2018 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | PNAS Plus Noack, Andreas Gericke, Birthe von Köckritz-Blickwede, Maren Menze, Arne Noack, Sandra Gerhauser, Ingo Osten, Felix Naim, Hassan Y. Löscher, Wolfgang Mechanism of drug extrusion by brain endothelial cells via lysosomal drug trapping and disposal by neutrophils |
title | Mechanism of drug extrusion by brain endothelial cells via lysosomal drug trapping and disposal by neutrophils |
title_full | Mechanism of drug extrusion by brain endothelial cells via lysosomal drug trapping and disposal by neutrophils |
title_fullStr | Mechanism of drug extrusion by brain endothelial cells via lysosomal drug trapping and disposal by neutrophils |
title_full_unstemmed | Mechanism of drug extrusion by brain endothelial cells via lysosomal drug trapping and disposal by neutrophils |
title_short | Mechanism of drug extrusion by brain endothelial cells via lysosomal drug trapping and disposal by neutrophils |
title_sort | mechanism of drug extrusion by brain endothelial cells via lysosomal drug trapping and disposal by neutrophils |
topic | PNAS Plus |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187170/ https://www.ncbi.nlm.nih.gov/pubmed/30254169 http://dx.doi.org/10.1073/pnas.1719642115 |
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