scholarly journals ATP Binding Enables Substrate Release from Multidrug Resistance Protein 1

Cell ◽  
2018 ◽  
Vol 172 (1-2) ◽  
pp. 81-89.e10 ◽  
Author(s):  
Zachary Lee Johnson ◽  
Jue Chen
Keyword(s):  
Multidrug Resistance ◽  
Atp Binding ◽  
Multidrug Resistance Protein ◽  
Multidrug Resistance Protein 1 ◽  
Resistance Protein

scholarly journals The Effect of Nanosystems on ATP-Binding Cassette Transporters: Understanding the Influence of Nanosystems on Multidrug Resistance Protein-1 and P-glycoprotein

2020 ◽  
Vol 21 (7) ◽  
pp. 2630
Author(s):  
Francisco V.C. Mello ◽  
Gabriela N. de Moraes ◽  
Raquel C. Maia ◽  
Jennifer Kyeremateng ◽  
Surtaj Hussain Iram ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Abc Transporters ◽  
Graphene Quantum Dots ◽  
Atp Binding ◽  
Multidrug Resistance Protein ◽  
Membrane Expression ◽  
Multidrug Resistance Protein 1 ◽  
P Glycoprotein ◽  
Resistance Protein ◽  
Atp Binding Cassette

The cancer multidrug resistance is involved in the failure of several treatments during cancer treatment. It is a phenomenon that has been receiving great attention in the last years due to the sheer amount of mechanisms discovered and involved in the process of resistance which hinders the effectiveness of many anti-cancer drugs. Among the mechanisms involved in the multidrug resistance, the participation of ATP-binding cassette (ABC) transporters is the main one. The ABC transporters are a group of plasma membrane and intracellular organelle proteins involved in the process of externalization of substrates from cells, which are expressed in cancer. They are involved in the clearance of intracellular metabolites as ions, hormones, lipids and other small molecules from the cell, affecting directly and indirectly drug absorption, distribution, metabolism and excretion. Other mechanisms responsible for resistance are the signaling pathways and the anti- and pro-apoptotic proteins involved in cell death by apoptosis. In this study we evaluated the influence of three nanosystem (Graphene Quantum Dots (GQDs), mesoporous silica (MSN) and poly-lactic nanoparticles (PLA)) in the main mechanism related to the cancer multidrug resistance such as the Multidrug Resistance Protein-1 and P-glycoprotein. We also evaluated this influence in a group of proteins involved in the apoptosis-related resistance including cIAP-1, XIAP, Bcl-2, BAK and Survivin proteins. Last, colonogenic and MTT (3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide) assays have also been performed. The results showed, regardless of the concentration used, GQDs, MSN and PLA were not cytotoxic to MDA-MB-231 cells and showed no impairment in the colony formation capacity. In addition, it has been observed that P-gp membrane expression was not significantly altered by any of the three nanomaterials. The results suggest that GQDs nanoparticles would be suitable for the delivery of other multidrug resistance protein 1 (MRP1) substrate drugs that bind to the transporter at the same binding pocket, while MSN can strongly inhibit doxorubicin efflux by MRP1. On the other hand, PLA showed moderate inhibition of doxorubicin efflux by MRP1 suggesting that this nanomaterial can also be useful to treat MDR (Multidrug resistance) due to MRP1 overexpression.

scholarly journals Multidrug resistance protein 1 regulates lipid asymmetry in erythrocyte membranes

2000 ◽  
Vol 350 (2) ◽  
pp. 531-535 ◽  
Author(s):  
David W. C. DEKKERS ◽  
Paul COMFURIUS ◽  
Rein G. J. VAN GOOL ◽  
Edouard M. BEVERS ◽  
Robert F. A. ZWAAL
Keyword(s):  
Multidrug Resistance ◽  
Erythrocyte Membrane ◽  
Erythrocyte Membranes ◽  
Multidrug Resistance Protein ◽  
Multidrug Resistance Protein 1 ◽  
Lipid Asymmetry ◽  
Appreciable Change ◽  
Outer Leaflet ◽  
Resistance Protein ◽  
Phospholipid Distribution

The role of multidrug resistance protein 1 (MRP1) in the maintenance of transbilayer lipid asymmetry in the erythrocyte membrane was investigated. The transbilayer distribution of endogenous phospholipids and [(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]hexanoyl (NBD)-labelled lipid analogues was compared in the absence and the presence of inhibitors of MRP1. At equilibrium the transbilayer distribution of the NBD analogues (in the absence of MRP1 inhibitors) was very similar to that of the endogenous lipids. Inhibition of MRP1 by verapamil or indomethacin resulted in a shift in the amount of probe that was internalized: approx. 50% of NBD-labelled phosphatidylcholine (PtdCho) and 9% of NBD-sphingomyelin (NBD-Spm) were no longer extractable by BSA in cells treated with inhibitor, in comparison with 25% and 3% for control cells respectively. To verify whether inhibition of MRP1 also affected the distribution of the endogenous phospholipids, phospholipase A2 and sphingomyelinase were used to assess the amount of each of the various lipid classes present in the membrane outer leaflet. No shift in phospholipid distribution was observed after 5h of incubation with verapamil or indomethacin. However, after 48h of incubation with these inhibitors, significantly smaller amounts of PtdCho and Spm were present in the outer membrane leaflet. No appreciable change was observed in the distribution of phosphatidylethanolamine or phosphatidylserine. Decreased hydrolysis of PtdCho and Spm was not due to endovesicle formation, as revealed by electron microscopy. This is the first report to show that MRP1 has a role in the maintenance of the outwards orientation of endogenous choline-containing phospholipids in the erythrocyte membrane.

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