Influence of doxorubicin on model cell membrane properties: insights from in vitro and in silico studies

Abstract Despite doxorubicin being commonly used in chemotherapy there still remain significant holes in our knowledge regarding its delivery efficacy and an observed resistance mechanism that is postulated to involve the cell membrane. One possible mechanism is the efflux by protein P-gp, which is...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Ana Catarina Alves, Aniket Magarkar, Miguel Horta, Jose L. F. C. Lima, Alex Bunker, Cláudia Nunes, Salette Reis
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3fa980605e2b4fc4a7f70719b932c105
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:3fa980605e2b4fc4a7f70719b932c105
record_format	dspace
spelling	oai:doaj.org-article:3fa980605e2b4fc4a7f70719b932c1052021-12-02T15:05:39ZInfluence of doxorubicin on model cell membrane properties: insights from in vitro and in silico studies10.1038/s41598-017-06445-z2045-2322https://doaj.org/article/3fa980605e2b4fc4a7f70719b932c1052017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06445-zhttps://doaj.org/toc/2045-2322Abstract Despite doxorubicin being commonly used in chemotherapy there still remain significant holes in our knowledge regarding its delivery efficacy and an observed resistance mechanism that is postulated to involve the cell membrane. One possible mechanism is the efflux by protein P-gp, which is found predominantly in cholesterol enriched domains. Thereby, a hypothesis for the vulnerability of doxorubicin to efflux through P-gp is its enhanced affinity for the ordered cholesterol rich regions of the plasma membrane. Thus, we have studied doxorubicin’s interaction with model membranes in a cholesterol rich, ordered environment and in liquid-disordered cholesterol poor environment. We have combined three separate experimental protocols: UV-Vis spectrophotometry, fluorescence quenching and steady-state anisotropy and computational molecular dynamics modeling. Our results show that the presence of cholesterol induces a change in membrane structure and doesn’t impair doxorubicin’s membrane partitioning, but reduces drug’s influence on membrane fluidity without directly interacting with it. It is thus possible that the resistance mechanism that lowers the efficacy of doxorubicin, results from an increased density in membrane regions where the efflux proteins are present. This work represents a successful approach, combining experimental and computational studies of membrane based systems to unveil the behavior of drugs and candidate drug molecules.Ana Catarina AlvesAniket MagarkarMiguel HortaJose L. F. C. LimaAlex BunkerCláudia NunesSalette ReisNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ana Catarina Alves Aniket Magarkar Miguel Horta Jose L. F. C. Lima Alex Bunker Cláudia Nunes Salette Reis Influence of doxorubicin on model cell membrane properties: insights from in vitro and in silico studies
description	Abstract Despite doxorubicin being commonly used in chemotherapy there still remain significant holes in our knowledge regarding its delivery efficacy and an observed resistance mechanism that is postulated to involve the cell membrane. One possible mechanism is the efflux by protein P-gp, which is found predominantly in cholesterol enriched domains. Thereby, a hypothesis for the vulnerability of doxorubicin to efflux through P-gp is its enhanced affinity for the ordered cholesterol rich regions of the plasma membrane. Thus, we have studied doxorubicin’s interaction with model membranes in a cholesterol rich, ordered environment and in liquid-disordered cholesterol poor environment. We have combined three separate experimental protocols: UV-Vis spectrophotometry, fluorescence quenching and steady-state anisotropy and computational molecular dynamics modeling. Our results show that the presence of cholesterol induces a change in membrane structure and doesn’t impair doxorubicin’s membrane partitioning, but reduces drug’s influence on membrane fluidity without directly interacting with it. It is thus possible that the resistance mechanism that lowers the efficacy of doxorubicin, results from an increased density in membrane regions where the efflux proteins are present. This work represents a successful approach, combining experimental and computational studies of membrane based systems to unveil the behavior of drugs and candidate drug molecules.
format	article
author	Ana Catarina Alves Aniket Magarkar Miguel Horta Jose L. F. C. Lima Alex Bunker Cláudia Nunes Salette Reis
author_facet	Ana Catarina Alves Aniket Magarkar Miguel Horta Jose L. F. C. Lima Alex Bunker Cláudia Nunes Salette Reis
author_sort	Ana Catarina Alves
title	Influence of doxorubicin on model cell membrane properties: insights from in vitro and in silico studies
title_short	Influence of doxorubicin on model cell membrane properties: insights from in vitro and in silico studies
title_full	Influence of doxorubicin on model cell membrane properties: insights from in vitro and in silico studies
title_fullStr	Influence of doxorubicin on model cell membrane properties: insights from in vitro and in silico studies
title_full_unstemmed	Influence of doxorubicin on model cell membrane properties: insights from in vitro and in silico studies
title_sort	influence of doxorubicin on model cell membrane properties: insights from in vitro and in silico studies
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/3fa980605e2b4fc4a7f70719b932c105
work_keys_str_mv	AT anacatarinaalves influenceofdoxorubicinonmodelcellmembranepropertiesinsightsfrominvitroandinsilicostudies AT aniketmagarkar influenceofdoxorubicinonmodelcellmembranepropertiesinsightsfrominvitroandinsilicostudies AT miguelhorta influenceofdoxorubicinonmodelcellmembranepropertiesinsightsfrominvitroandinsilicostudies AT joselfclima influenceofdoxorubicinonmodelcellmembranepropertiesinsightsfrominvitroandinsilicostudies AT alexbunker influenceofdoxorubicinonmodelcellmembranepropertiesinsightsfrominvitroandinsilicostudies AT claudianunes influenceofdoxorubicinonmodelcellmembranepropertiesinsightsfrominvitroandinsilicostudies AT salettereis influenceofdoxorubicinonmodelcellmembranepropertiesinsightsfrominvitroandinsilicostudies
_version_	1718388760308088832

Influence of doxorubicin on model cell membrane properties: insights from in vitro and in silico studies

Ejemplares similares