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Screening dietary flavonoids for the reversal of P-glycoprotein-mediated multidrug resistance in cancer.
- Source :
-
Molecular bioSystems [Mol Biosyst] 2016 Jul 19; Vol. 12 (8), pp. 2458-70. - Publication Year :
- 2016
-
Abstract
- P-Glycoprotein (P-gp) serves as a therapeutic target for the development of inhibitors to overcome multidrug resistance in cancer cells. Although various screening procedures have been practiced so far to develop first three generations of P-gp inhibitors, their toxicity and drug interaction profiles are still a matter of concern. To address the above important problem of developing safe and effective P-gp inhibitors, we have made systematic computational and experimental studies on the interaction of natural phytochemicals with human P-gp. Molecular docking and QSAR studies were carried out for 40 dietary phytochemicals in the drug-binding site of the transmembrane domains (TMDs) of P-gp. Dietary flavonoids exhibit better interactions with homology modeled human P-gp. Based on the computational analysis, selected flavonoids were tested for their inhibitory potential against P-gp transport function in drug resistant cell lines using calcein-AM and rhodamine 123 efflux assays. It has been found that quercetin and rutin were the highly desirable flavonoids for the inhibition of P-gp transport function and they significantly reduced resistance in cytotoxicity assays to paclitaxel in P-gp overexpressing MDR cell lines. Hence, quercetin and rutin may be considered as potential chemosensitizing agents to overcome multidrug resistance in cancer.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors
ATP Binding Cassette Transporter, Subfamily B, Member 1 chemistry
ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism
Antineoplastic Agents chemistry
Binding Sites
Catalytic Domain
Cell Line, Tumor
Computer Simulation
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Flavonoids chemistry
Humans
Ligands
Models, Molecular
Molecular Docking Simulation
Protein Binding
Protein Conformation
Structure-Activity Relationship
ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics
Antineoplastic Agents pharmacology
Dietary Supplements
Drug Resistance, Neoplasm genetics
Flavonoids pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1742-2051
- Volume :
- 12
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Molecular bioSystems
- Publication Type :
- Academic Journal
- Accession number :
- 27216424
- Full Text :
- https://doi.org/10.1039/c6mb00187d