Pentagalloyl Glucose-Targeted Inhibition of P-Glycoprotein and Re-Sensitization of Multidrug-Resistant Leukemic Cells (K562/ADR) to Doxorubicin: In Silico and Functional Studies

Pentagalloyl Glucose-Targeted Inhibition of P-Glycoprotein and Re-Sensitization of Multidrug-Resistant Leukemic Cells (K562/ADR) to Doxorubicin: In Silico and Functional Studies

Combining phytochemicals with chemotherapeutic drugs has demonstrated the potential to surmount drug resistance. In this paper, we explore the efficacy of pentagalloyl glucose (PGG) in modulating P-gp and reversing multidrug resistance (MDR) in drug-resistant leukemic cells (K562/ADR). The cytotoxic...

Full description

Saved in:
Bibliographic Details
Published in:Pharmaceuticals (Basel, Switzerland) Vol. 16; no. 9; p. 1192
Main Authors: Dechsupa, Nathupakorn, Khamto, Nopawit, Chawapun, Pornthip, Siriphong, Sadanon, Innuan, Phattarawadee, Suwan, Authaphinya, Luangsuep, Thitiworada, Photilimthana, Nichakorn, Maita, Witchayaporn, Thanacharttanatchaya, Rossarin, Sangthong, Padchanee, Meepowpan, Puttinan, Udomtanakunchai, Chatchanok, Kantapan, Jiraporn
Format: Journal Article
Language:English
Published: Basel MDPI AG 22-08-2023
MDPI
Subjects:
Cancer therapies
Care and treatment
Clinical outcomes
Cytotoxicity
Diagnosis
Dosage and administration
Doxorubicin
Drug dosages
Drug resistance
Drug therapy
Glucose
Glycoproteins
Health aspects
Leukemia
Medical research
P-glycoprotein
Patient outcomes
pentagalloyl glucose
PGG
Polyphenols
Proteins
sensitizer
Testing
Thailand
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Combining phytochemicals with chemotherapeutic drugs has demonstrated the potential to surmount drug resistance. In this paper, we explore the efficacy of pentagalloyl glucose (PGG) in modulating P-gp and reversing multidrug resistance (MDR) in drug-resistant leukemic cells (K562/ADR). The cytotoxicity of PGG was evaluated using a CCK-8 assay, and cell apoptosis was assessed using flow cytometry. Western blotting was used to analyze protein expression levels. P-glycoprotein (P-gp) activity was evaluated by monitoring the kinetics of P-gp-mediated efflux of pirarubicin (THP). Finally, molecular docking, molecular dynamics simulation, and molecular mechanics with generalized Born and surface area solvation (MM-GBSA) calculation were conducted to investigate drug–protein interactions. We found that PGG selectively induced cytotoxicity in K562/ADR cells and enhanced sensitivity to doxorubicin (DOX), indicating its potential as a reversal agent. PGG reduced the expression of P-gp and its gene transcript levels. Additionally, PGG inhibited P-gp-mediated efflux and increased intracellular drug accumulation in drug-resistant cells. Molecular dynamics simulations and MM-GBSA calculation provided insights into the binding affinity of PGG to P-gp, suggesting that PGG binds tightly to both the substrate and the ATP binding sites of P-gp. These findings support the potential of PGG to target P-gp, reverse drug resistance, and enhance the efficacy of anticancer therapies.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1424-8247
1424-8247
DOI:10.3390/ph16091192