Abstract |
P-glycoprotein (P-gp or MDR1) is an ATP-binding cassette ( ABC) transporter. It is involved in the efflux of several anticancer drugs, which leads to chemotherapy failure and multidrug resistance (MDR) in cancer cells. Representative secondary metabolites (SM) including phenolics (EGCG and thymol), terpenoids ( menthol, aromadendrene, β- sitosterol-O- glucoside, and β- carotene), and alkaloids ( glaucine, harmine, and sanguinarine) were evaluated as potential P-gp inhibitors (transporter activity and expression level) in P-gp expressing Caco-2 and CEM/ADR5000 cancer cell lines. Selected SM increased the accumulation of the rhodamine 123 (Rho123) and calcein-AM (CAM) in a dose dependent manner in Caco-2 cells, indicating that they act as competitive inhibitors of P-gp. Non-toxic concentrations of β- carotene (40μM) and sanguinarine (1μM) significantly inhibited Rho123 and CAM efflux in CEM/ADR5000 cells by 222.42% and 259.25% and by 244.02% and 290.16%, respectively relative to verapamil (100%). Combination of the saponin digitonin (5μM), which also inhibits P-gp, with SM significantly enhanced the inhibition of P-gp activity. The results were correlated with the data obtained from a quantitative analysis of MDR1 expression. Both compounds significantly decreased mRNA levels of the MDR1 gene to 48% (p<0.01) and 46% (p<0.01) in Caco-2, and to 61% (p<0.05) and 1% (p<0.001) in CEM/ADR5000 cells, respectively as compared to the untreated control (100%). Combinations of digitonin with SM resulted in a significant down-regulation of MDR1. Our findings provide evidence that the selected SM interfere directly and/or indirectly with P-gp function. Combinations of different P-gp substrates, such as digitonin alone and together with the set of SM, can mediate MDR reversal in cancer cells.
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Authors | Safaa Yehia Eid, Mahmoud Zaki El-Readi, Essam Eldin Mohamed Nour Eldin, Sameer Hassan Fatani, Michael Wink |
Journal | Phytomedicine : international journal of phytotherapy and phytopharmacology
(Phytomedicine)
Vol. 21
Issue 1
Pg. 47-61
(Dec 15 2013)
ISSN: 1618-095X [Electronic] Germany |
PMID | 23999162
(Publication Type: Journal Article)
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Copyright | Copyright © 2013 Elsevier GmbH. All rights reserved. |
Chemical References |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Alkaloids
- Antineoplastic Agents, Phytogenic
- Benzophenanthridines
- Drug Combinations
- Fluoresceins
- Isoquinolines
- Phenols
- Phytochemicals
- Plant Extracts
- RNA, Messenger
- Terpenes
- beta Carotene
- calcein AM
- Rhodamine 123
- sanguinarine
- Digitonin
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Topics |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
(genetics, metabolism)
- Alkaloids
(pharmacology, therapeutic use)
- Antineoplastic Agents, Phytogenic
(pharmacology, therapeutic use)
- Benzophenanthridines
(pharmacology, therapeutic use)
- Caco-2 Cells
- Colonic Neoplasms
(drug therapy, genetics, metabolism)
- Digitonin
(pharmacology, therapeutic use)
- Dose-Response Relationship, Drug
- Drug Combinations
- Drug Resistance, Multiple
(drug effects)
- Drug Resistance, Neoplasm
(drug effects)
- Drug Synergism
- Fluoresceins
(metabolism)
- Humans
- Isoquinolines
(pharmacology, therapeutic use)
- Leukemia
(drug therapy, genetics, metabolism)
- Phenols
(pharmacology, therapeutic use)
- Phytochemicals
(pharmacology, therapeutic use)
- Phytotherapy
- Plant Extracts
(pharmacology, therapeutic use)
- RNA, Messenger
(metabolism)
- Rhodamine 123
(metabolism)
- Terpenes
(pharmacology, therapeutic use)
- beta Carotene
(pharmacology, therapeutic use)
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