Effect of the modulation of the membrane lipid composition on the localization and function of P-glycoprotein in mdr1-MDCK cells

Kamau, Sarah W.; KrÃ?mer, Stefanie; GÃ?nthert, Maja; Wunderli‐Allenspach, Heidi

doi:10.1290/0502016

Cited by 18 publications

(26 citation statements)

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“…Thus, whilst nanoparticles potentially change the conformation of the cell membrane, resulting in a disruption of cellular processes and membrane integrity [23,24], most interactions with the cell membrane do not cause any membrane disruption or extraction of the protein from the plasmalemma, as previously observed in the case of cyclodextrins [25]. This was confirmed by Western blot analysis of the cells and their supernatant.…”

Section: Discussionsupporting

confidence: 70%

Nanoparticles attenuate P-glycoprotein/MDR1 function in A549 human alveolar epithelial cells

Salomon

Ehrhardt

2011

European Journal of Pharmaceutics and Biopharmaceutics

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P-glycoprotein/MDR1 (P-gp) is a well characterised membrane transporter relevant in drug disposition and multi-drug resistance. In this study, we aimed to investigate in how far nanoparticulates impair the function of the P-gp transport system, and which particle properties govern these interactions.Expression and function of P-gp was confirmed in A549 cell monolayers. Rhodamine 123 (Rh123) release studies were carried out in the presence of known inhibitors of Pgp function (i.e., cyclosporine A and verapamil), under ATP depletion (NaN 3 /DOG) and after acute exposure to nanoparticles (NPs) with different surface modifications, ζ-potentials and sizes (plain, carboxylated, and amine-and sulphate-modified). The cytotoxic potential of NPs on A549 monolayers was evaluated by MTT assay. The effects on P-gp protein level, after incubation with NPs, were investigated by Western blot analysis of A549 cell lysate and supernatant. Cellular retention of Rh123 was significantly (P < 0.05) increased in the presence of carboxylated (100 nm), amine-and sulphate-modified NPs. A slight, but not significant, decrease in Rh123 release was also observed for plain latex and carboxylated (500 nm)NPs. The MTT assay demonstrated that most NPs caused only marginal levels of cytotoxicity (78-88% cell viability); the positively charged amine-NPs, however, were considerably more cytotoxic. Western blot showed that NPs did not cause any cell membrane disruption.Our findings suggest that nanomaterials can attenuate membrane transporter function depending on their size and surface properties and hence, might influence disposition of xenobiotics as well as endogenous substrates.

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Section: Discussionsupporting

confidence: 70%

Nanoparticles attenuate P-glycoprotein/MDR1 function in A549 human alveolar epithelial cells

Salomon

Ehrhardt

2011

European Journal of Pharmaceutics and Biopharmaceutics

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“…It was later proposed that GSL/cholesterol trafficking plays a more pervasive role in protein sorting during intracellular vesicular trafficking (Sillence et al 2002). Inhibition of cellular GSL biosynthesis results in the loss of cell surface immunodetection of MDR1 (Wojtal et al 2006;De Rosa et al 2008) and its loss from lipid rafts (Kamau et al 2005), suggesting an intimate relationship between these processes, potentially mediated by the lipid raft requirement for MDR1 function (Kamau et al 2005). In MDR1-MDCK cells, cell surface MDR1 colocalized with globotriaosyl ceramide (Gb 3 ), and a soluble analog of Gb 3 proved an MDR1inhibitor (De Rosa et al 2008).…”

Section: Gsls and Intracellular Protein Traffickingmentioning

confidence: 99%

Glycosphingolipid Functions

Lingwood¹

2011

Cold Spring Harbor Perspectives in Biology

108

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“…Membrane changes may perturb either the structure of P-gp or the conformation of the drug, changing its recognition by P-gp or sequester drugs into a membrane subdomain from which P-gp is excluded. Changes in membrane dynamics might allow drugs to cross the membrane more rapidly than P-gp can efflux them, subverting resistance [29]. The critical parameter for determining whether a cell resists a drug is not the extracellular concentration of drug but the intracellular concentration set by the equilibrium between drug permeation through the membrane and efflux by all the cell's competent transporters.…”

Section: The Transport Mechanism(s) Of Abc Transportersmentioning

confidence: 99%

Preface: the concept and consequences of multidrug resistance

Sheps¹,

Ling²

2006

Pflugers Arch - Eur J Physiol

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The problem of multidrug resistance (MDR) in human cancers led to the discovery 30 years ago of a single protein P-glycoprotein (P-gp), capable of mediating resistance to multiple structurally diverse drugs. P-gp became the archetypal eukaryotic ABC transporter gene, and studies of P-gp and related ABC transporters in both eukaryotes and bacteria have led to a basic mechanistic understanding of the molecular basis of MDR. Particular milestones along the way have been the identification of the homology between P-gp and bacterial transport proteins, the purification and functional reconstitution of P-gp into synthetic lipid systems, and the development of targeted therapies that attempt to overcome MDR by inhibiting Pgp. This preface places into this context some of the less well-explored themes developed in the MDR field, particularly various alternative models of P-gp action, evidence for parallel physiological roles for P-gp, and the unusual relationship between the substrate recognition capabilities of ABC transporters and their evolutionary history.

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Effect of the modulation of the membrane lipid composition on the localization and function of P-glycoprotein in mdr1-MDCK cells

Cited by 18 publications

References 0 publications

Nanoparticles attenuate P-glycoprotein/MDR1 function in A549 human alveolar epithelial cells

Nanoparticles attenuate P-glycoprotein/MDR1 function in A549 human alveolar epithelial cells

Glycosphingolipid Functions

Preface: the concept and consequences of multidrug resistance

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