Discovery of the inhibitory effect of a phosphatidylinositol derivative on P-glycoprotein by virtual screening followed by in vitro cellular studies

Xavier Lucas, Silke Simon, Rolf Schubert, Stefan Günther

Research output: Contribution to journalArticle

7 Citations (Scopus)
167 Downloads (Pure)

Abstract

P-glycoprotein is capable of effluxing a broad range of cytosolic and membrane penetrating xenobiotic substrates, thus leading to multi-drug resistance and posing a threat for the therapeutic treatment of several diseases, including cancer and central nervous disorders. Herein, a virtual screening campaign followed by experimental validation in Caco-2, MDKCII, and MDKCII mdr1 transfected cell lines has been conducted for the identification of novel phospholipids with P-gp transportation inhibitory activity. Phosphatidylinositol-(1,2-dioctanoyl)-sodium salt (8∶0 PI) was found to significantly inhibit transmembrane P-gp transportation in vitro in a reproducible-, cell line-, and substrate-independent manner. Further tests are needed to determine whether this and other phosphatidylinositols could be co-administered with oral drugs to successfully increase their bioavailability. Moreover, as phosphatidylinositols and phosphoinositides are present in the human diet and are known to play an important role in signal transduction and cell motility, our finding could be of substantial interest for nutrition science as well.

Original languageEnglish
Article numbere60679
Number of pages8
JournalPLoS ONE
Volume8
Issue number4
DOIs
Publication statusPublished - 9 Apr 2013

Keywords

  • Biological transport
  • Caco-2 cells
  • Cell line
  • Chemistry, Pharmaceutical
  • Cryoelectron microscopy
  • Digoxin
  • Drug discovery
  • Drug resistance, Multiple
  • Fluoresceins
  • Humans
  • Molecular docking simulation
  • P-Glycoproteins
  • Permeability
  • Phosphatidylinositols
  • Phospholipids
  • Protein binding
  • Protein conformation
  • Journal article
  • Research support, Non-U.S. Gov't

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