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Inhibition of multidrug resistance-associated protein (MRP) functional activity with pluronic block copolymers
D W Miller1, E V Batrakova, A V Kabanov
1Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha 68198-6025, USA.
Purpose:
Using monolayers of human pancreatic adenocarcinoma cells (Panc-1) that express multidrug resistance-associated protein (MRP), the present work investigates the effects of Pluronic block copolymers on the functional activity of MRP.
Methods:
The studies examined the accumulation and efflux of the MRP selective probe fluorescein (FLU) in Panc-1 cell monolayers with and without Pluronic P85 (P85), Pluronic L81 (L81) and Pluronic F108 (F108).
Results:
Treatment of Panc-1 cells with P85 resulted in concentration-dependent increases in FLU accumulation and elimination of FLU sequestration in vesicular compartments in these cells. The effects of P85 were selective for FLU in the Panc-1 cell monolayers. Inhibition of MRP-mediated transport was dependent on the composition of Pluronic block copolymer: the more hydrophobic copolymer had the greater effect on FLU uptake in Panc-1 monolayers (L81 > P85 > F108).
Conclusions:
This paper demonstrates for the first time that Pluronic block copolymers inhibit multidrug resistance-associated protein (MRP). The similarities in the effects of Pluronic block copolymers on MRP and P-glycoprotein drug efflux systems suggest that a single unifying mechanism may explain the inhibition observed.
Insights
Pluronic block copolymers were found to inhibit multidrug resistance-associated protein (MRP) in pancreatic cancer cells. This suggests a potential new strategy for overcoming drug resistance in cancer therapy.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Multidrug resistance-associated protein (MRP) is a key transporter involved in cancer drug resistance.
- Pancreatic adenocarcinoma cells (Panc-1) express MRP, making them a relevant model for studying drug transport.
- Pluronic block copolymers are amphiphilic polymers with potential applications in drug delivery and modulation of cellular processes.
Purpose of the Study:
- To investigate the effects of Pluronic block copolymers on the functional activity of MRP in human pancreatic adenocarcinoma cells (Panc-1).
- To determine if Pluronic block copolymers can inhibit MRP-mediated transport.
Main Methods:
- Panc-1 cell monolayers were treated with different Pluronic block copolymers (P85, L81, F108).
- Accumulation and efflux of the MRP-selective probe fluorescein (FLU) were measured.
- The impact of Pluronic treatment on FLU sequestration in vesicular compartments was assessed.
Main Results:
- Pluronic P85 increased FLU accumulation and reduced its sequestration in vesicular compartments in Panc-1 cells.
- The inhibitory effect on MRP-mediated transport was dependent on the hydrophobicity of the Pluronic copolymer, with more hydrophobic variants showing greater inhibition (L81 > P85 > F108).
- The effects observed were specific to FLU transport in the Panc-1 cell monolayers.
Conclusions:
- Pluronic block copolymers effectively inhibit MRP-mediated transport in pancreatic cancer cells.
- The findings suggest a potential unifying mechanism for Pluronic inhibition of both MRP and P-glycoprotein efflux systems.
- This study demonstrates a novel application of Pluronic block copolymers in overcoming multidrug resistance.