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

• Type: Article in International Scientific Journal
• Date: 2017

Authors

Alves, AC (Author) Other; Magarkar, A (Author) Other; Horta, M (Author) Other; Lima, JLFC (Author) FMUP; Bunker, A (Author) Other; Nunes, C (Author) Other; Salette Reis (Author) FFUP

Journal

Title: Scientific Reports

Vol. 7

ISSN: 2045-2322

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 8 Citations

Scopus - 27 Citations

Other information

Authenticus ID: P-00N-G7G

DOI: 10.1038/s41598-017-06445-z

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11