scholarly journals In silico and in vitro identification of secoisolariciresinol as a re-sensitizer of P-glycoprotein-dependent doxorubicin-resistance NCI/ADR-RES cancer cells

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9163 ◽  
Author(s):  
Mohamed A. Morsy ◽  
Azza A.K. El-Sheikh ◽  
Ahmed R.N. Ibrahim ◽  
Katharigatta N. Venugopala ◽  
Mahmoud Kandeel
Keyword(s):  
Cancer Cells ◽  
Md Simulation ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
Binding Domains ◽  
P Glycoprotein ◽  
Resistance Protein ◽  
Substrate Inhibitor ◽  
Dose Dependent

P-glycoprotein (P-gp) is one of the highly expressed cancer cell efflux transporters that cause the failure of chemotherapy. To reverse P-gp induced multidrug resistance, we employed a flaxseed-derived lignan; secoisolariciresinol (SECO) that acts as an inhibitor of breast cancer resistance protein; another efflux transporter that shares some substrate/inhibitor specificity with P-gp. Molecular dynamics (MD) simulation identified SECO as a possible P-gp inhibitor. Comparing root mean square deviation (RMSD) of P-gp bound with SECO with that bound to its standard inhibitor verapamil showed that fluctuations in RMSD were lower in P-gp bound to SECO demonstrating higher stability of the complex of P-gp with SECO. In addition, the superimposition of P-gp structures after MD simulation showed that the nucleotide-binding domains of P-gp bound to SECO undertook a more central closer position compared with that bound to verapamil. Using rhodamine efflux assay on NCI/ADR-RES cancer cells, SECO was confirmed as a P-gp inhibitor, where cells treated with 25 or 50 µM of SECO showed significantly higher fluorescence intensity compared to control. Using MTT assay, SECO alone showed dose-dependent cytotoxicity, where 25 or 50 µM of SECO caused significantly less NCI/ADR-RES cellular viability compared to control. Furthermore, when 50 µM of SECO was added to doxorubicin (DOX), an anticancer drug, SECO significantly enhanced DOX-induced cytotoxicity compared to DOX alone. The combination index calculated by CompuSyn software indicated synergism between DOX and SECO. Our results suggest SECO as a novel P-gp inhibitor that can re-sensitize cancer cells during DOX chemotherapy.

scholarly journals P-Glycoprotein and Breast Cancer Resistance Protein Restrict Apical-to-Basolateral Permeability of Human Brain Endothelium to Amyloid-β

2009 ◽  
Vol 29 (6) ◽  
pp. 1079-1083 ◽  
Author(s):  
Leon M Tai ◽  
A Jane Loughlin ◽  
David K Male ◽  
Ignacio A Romero
Keyword(s):  
Breast Cancer ◽  
Human Brain ◽  
Breast Cancer Resistance Protein ◽  
Amyloid Β ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Resistance Protein ◽  
The Brain

The clearance of amyloid beta (Aβ) from the brain represents a novel therapeutic target for Alzheimer's disease. Conflicting data exist regarding the contribution of adenosine triphosphatebinding cassette transporters to the clearance of Aβ through the blood-brain barrier. Therefore, we investigated whether Aβ could be a substrate for P-glycoprotein (P-gp) and/or for breast cancer resistance protein (BCRP) using a human brain endothelial cell line, hCMEC/D3. Inhibition of P-gp and BCRP increased apical-to-basolateral, but not basolateral-to-apical, permeability of hCMEC/D3 cells to 125l Aβ 1–40. Our in vitro data suggest that P-gp and BCRP might act to prevent the blood-borne Aβ 1–40 from entering the brain.

Oleic acid increases uptake and decreases the P-gp-mediated efflux of the veterinary anthelmintic Ivermectin

Drug Research ◽  
2018 ◽  
Vol 69 (03) ◽  
pp. 173-180 ◽  
Author(s):  
Bilal Houshaymi ◽  
Nadine Nasreddine ◽  
Mamdouh Kedees ◽  
Zeina Soayfane
Keyword(s):  
Oleic Acid ◽  
Intestinal Mucosa ◽  
Drug Formulation ◽  
Dependent Manner ◽  
Cancer Resistance ◽  
P Glycoprotein ◽  
Resistance Protein ◽  
Complex Micelles

AbstractThe bioavailability of ivermectin is modulated by lipid-based formulations and membrane efflux transporters such as Breast Cancer Resistance Protein and P-glycoprotein (BCRP and P-gp). We have investigated the effect of oleic acid on the uptake of ivermectin in vitro using Caco-2 cells and in vivo in the intestines of wild-type mice. Complex micelles (M) with oleic acid induced a significant increase (e. g. for M3 was 7-fold, p≤0.001) in the uptake of the drug in a time-dependent manner with no involvement of cholesterol in the mechanism. In vivo results showed a significant increase in the concentration of plasma and intestinal mucosa ivermectin (p≤0.01) in mice receiving oleic acid-based drug formulation. We also examined the expression of the drug efflux transporter, BCRP and P-gp in Caco-2 cells and found a significant decrease (p≤0.001) in their level in the presence of 5 mM oleic acid. Treatment of mice with oleic acid-based formulation showed a significant decrease in the activity of P-gp in the intestinal mucosa (p≤0.01). This study highlighted the effect of oleic acid in decreasing the expression and the activity of P-gp-mediated ivermectin efflux and in limiting the drug absorption by increasing its uptake and bioavailability in Caco-2 cells and intestine, respectively.

scholarly journals Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter Modulators

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3364 ◽  
Author(s):  
Bruno M. F. Gonçalves ◽  
David S. P. Cardoso ◽  
Maria-José U. Ferreira
Keyword(s):  
Multidrug Resistance ◽  
Natural Product ◽  
Abc Transporter ◽  
Efflux Pumps ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
Multidrug Resistance Protein 1 ◽  
P Glycoprotein ◽  
Resistance Protein

Multidrug resistance (MDR) in cancer is one of the main limitations for chemotherapy success. Numerous mechanisms are behind the MDR phenomenon wherein the overexpression of the ATP-binding cassette (ABC) transporter proteins P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance protein 1 (MRP1) is highlighted as a prime factor. Natural product-derived compounds are being addressed as promising ABC transporter modulators to tackle MDR. Flavonoids and terpenoids have been extensively explored in this field as mono or dual modulators of these efflux pumps. Nitrogen-bearing moieties on these scaffolds were proved to influence the modulation of ABC transporters efflux function. This review highlights the potential of semisynthetic nitrogen-containing flavonoid and terpenoid derivatives as candidates for the design of effective MDR reversers. A brief introduction concerning the major role of efflux pumps in multidrug resistance, the potential of natural product-derived compounds in MDR reversal, namely natural flavonoid and terpenoids, and the effect of the introduction of nitrogen-containing groups are provided. The main modifications that have been performed during last few years to generate flavonoid and terpenoid derivatives, bearing nitrogen moieties, such as aliphatic, aromatic and heterocycle amine, amide, and related functional groups, as well as their P-gp, MRP1 and BCRP inhibitory activities are reviewed and discussed.

scholarly journals Multidrug Resistance Modulation Activity of Silybin Derivatives and Their Anti-Inflammatory Potential

Antioxidants ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 455 ◽  
Author(s):  
Simona Dobiasová ◽  
Kateřina Řehořová ◽  
Denisa Kučerová ◽  
David Biedermann ◽  
Kristýna Káňová ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Biological Activities ◽  
Biologically Active ◽  
Cancer Drug ◽  
Optical Isomers ◽  
Dependent Manner ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Dose Dependent

Silybin is considered to be the main biologically active component of silymarin. Its oxidized derivative 2,3-dehydrosilybin typically occurs in silymarin in small, but non-negligible amounts (up to 3%). Here, we investigated in detail complex biological activities of silybin and 2,3-dehydrosilybin optical isomers. Antioxidant activities of pure stereomers A and B of silybin and 2,3-dehydrosilybin, as well as their racemic mixtures, were investigated by using oxygen radical absorption capacity (ORAC) and cellular antioxidant activity (CAA) assay. All substances efficiently reduced nitric oxide production and cytokines (TNF-α, IL-6) release in a dose-dependent manner. Multidrug resistance (MDR) modulating potential was evaluated as inhibition of P-glycoprotein (P-gp) ATPase activity and regulation of ATP-binding cassette (ABC) protein expression. All the tested compounds showed strong dose-dependent inhibition of P-gp pump. Moreover, 2,3-dehydrosilybin A (30 µM) displayed the strongest sensitization of doxorubicin-resistant ovarian carcinoma. Despite these significant effects, silybin B was the only compound acting directly upon P-gp in vitro and also downregulating the expression of respective MDR genes. This compound altered the expression of P-glycoprotein (P-gp, ABCB1), multidrug resistance-associated protein 1 (MRP1, ABCC1) and breast cancer resistance protein (BCRP, ABCG2). 2,3-Dehydrosilybin AB exhibited the most effective inhibition of acetylcholinesterase activity. We can clearly postulate that silybin derivatives could serve well as modulators of a cancer drug-resistant phenotype.

Sign in / Sign up

Export Citation Format

Share Document