scholarly journals Human Immunodeficiency Virus Protease Inhibitors Interact with ATP Binding Cassette Transporter 4/Multidrug Resistance Protein 4: A Basis for Unanticipated Enhanced Cytotoxicity

2013 ◽  
Vol 84 (3) ◽  
pp. 361-371 ◽  
Author(s):  
Yu Fukuda ◽  
Kazumasa Takenaka ◽  
Alex Sparreboom ◽  
Satish B. Cheepala ◽  
Chung-Pu Wu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Multidrug Resistance ◽  
Protease Inhibitors ◽  
Atp Binding ◽  
Multidrug Resistance Protein ◽  
Human Immunodeficiency Virus Protease ◽  
Atp Binding Cassette Transporter ◽  
Immunodeficiency Virus ◽  
Resistance Protein ◽  
Atp Binding Cassette

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 Multiple Mutations in the Human Immunodeficiency Virus Protease Gene Are Responsible for Decreased Susceptibility to Protease Inhibitors

1995 ◽  
Vol 6 (2) ◽  
pp. 80-88 ◽  
Author(s):  
R. W. King ◽  
S. Garber ◽  
D. L. Winslow ◽  
C. Reid ◽  
L. T. Bacheler ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitors ◽  
Clinical Isolate ◽  
Protease Gene ◽  
Human Immunodeficiency Virus Protease ◽  
Fold Reduction ◽  
Antiretroviral Drug ◽  
Immunodeficiency Virus ◽  
Hiv 1

The protease (PR) of the human immunodeficiency virus (HIV) is essential for replication of the virus, and accordingly has become an attractive target for the development of an antiretroviral drug. We have previously reported that passage of HIV-1 in the presence of increasing concentrations of the C-2 symmetrical, linear diol P9941 resulted in the isolation of virus with a valine-to-alanine change at position 82 (V82A) of the PR, and reduced sensitivity to certain PR inhibitors. In this study, we passaged four different variants of HIV-1 in increasing concentrations of XM323, and isolated variants with reduced sensitivity to inhibitors of PR. Twenty-three passages of HIV-1 (RF) in the presence of XM323 resulted in a variant that exhibited an approximately 100-fold reduction in susceptibility to XM323 and that contained V82F and I84V changes. When two other viruses, HIV-1 (RF41D2) and HIV-1(RF41E4), previously derived from HIV-1 (RF) by passage in the presence of P9941, were passaged in the presence of XM323, variants with V82A/L97V and M46L/V82A/L97V changes, respectively, were obtained. The M46L/V82A/L97V variant showed a 6-fold reduction in sensitivity to XM323, whereas the susceptibility of the V82A/L97V mutant remained unchanged. Seventeen passages of a clinical isolate of HIV-1, HIV-1 (Pat.E), in the presence of XM323 produced a V82F/L97V mutant with an approximately 9-fold reduction in sensitivity to XM323.

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