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Influence of combinations of digitonin with selected phenolics, terpenoids, and alkaloids on the expression and activity of P-glycoprotein in leukaemia and colon cancer cells

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), t... Full description

Journal Title: Phytomedicine (Stuttgart) 2013-12-15, Vol.21 (1), p.47-61
Main Author: Eid, Safaa Yehia
Other Authors: El-Readi, Mahmoud Zaki , Eldin, Essam Eldin Mohamed Nour , Fatani, Sameer Hassan , Wink, Michael
Format: Electronic Article Electronic Article
Language: English
Subjects:
Alkaloids
Alkaloids - pharmacology
Alkaloids - therapeutic use
Antineoplastic Agents, Phytogenic - pharmacology
Antineoplastic Agents, Phytogenic - therapeutic use
ATP-Binding Cassette, Sub-Family B, Member 1 - genetics
ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism
Benzophenanthridines - pharmacology
Benzophenanthridines - therapeutic use
beta Carotene - pharmacology
beta Carotene - therapeutic use
Caco-2 Cells
Cancer cells
Colon cancer
Colon cells
Colonic Neoplasms - drug therapy
Colonic Neoplasms - genetics
Colonic Neoplasms - metabolism
Digitonin
Digitonin - pharmacology
Digitonin - therapeutic use
Dose-Response Relationship, Drug
Drug Combinations
Drug Resistance, Multiple - drug effects
Drug Resistance, Neoplasm - drug effects
Drug Synergism
Drug therapy
Drug therapy, Combination
Fluoresceins - metabolism
Health aspects
Humans
Isoquinolines - pharmacology
Isoquinolines - therapeutic use
Leukaemia
Leukemia - drug therapy
Leukemia - genetics
Leukemia - metabolism
Multidrug resistance
Phenols - pharmacology
Phenols - therapeutic use
Physiological aspects
Phytochemicals - pharmacology
Phytochemicals - therapeutic use
Phytotherapy
Plant Extracts - pharmacology
Plant Extracts - therapeutic use
Rhodamine 123 - metabolism
RNA, Messenger - metabolism
Sanguinarine
Terpenes - pharmacology
Terpenes - therapeutic use
β-Carotene
Quelle: Alma/SFX Local Collection
Publisher: Germany: Elsevier GmbH
ID: ISSN: 0944-7113
Link: https://www.ncbi.nlm.nih.gov/pubmed/23999162
Zum Text:
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title: Influence of combinations of digitonin with selected phenolics, terpenoids, and alkaloids on the expression and activity of P-glycoprotein in leukaemia and colon cancer cells
format: Article
creator:
  • Eid, Safaa Yehia
  • El-Readi, Mahmoud Zaki
  • Eldin, Essam Eldin Mohamed Nour
  • Fatani, Sameer Hassan
  • Wink, Michael
subjects:
  • Alkaloids
  • Alkaloids - pharmacology
  • Alkaloids - therapeutic use
  • Antineoplastic Agents, Phytogenic - pharmacology
  • Antineoplastic Agents, Phytogenic - therapeutic use
  • ATP-Binding Cassette, Sub-Family B, Member 1 - genetics
  • ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism
  • Benzophenanthridines - pharmacology
  • Benzophenanthridines - therapeutic use
  • beta Carotene - pharmacology
  • beta Carotene - therapeutic use
  • Caco-2 Cells
  • Cancer cells
  • Colon cancer
  • Colon cells
  • Colonic Neoplasms - drug therapy
  • Colonic Neoplasms - genetics
  • Colonic Neoplasms - metabolism
  • Digitonin
  • Digitonin - pharmacology
  • Digitonin - therapeutic use
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Drug Resistance, Multiple - drug effects
  • Drug Resistance, Neoplasm - drug effects
  • Drug Synergism
  • Drug therapy
  • Drug therapy, Combination
  • Fluoresceins - metabolism
  • Health aspects
  • Humans
  • Isoquinolines - pharmacology
  • Isoquinolines - therapeutic use
  • Leukaemia
  • Leukemia - drug therapy
  • Leukemia - genetics
  • Leukemia - metabolism
  • Multidrug resistance
  • Phenols - pharmacology
  • Phenols - therapeutic use
  • Physiological aspects
  • Phytochemicals - pharmacology
  • Phytochemicals - therapeutic use
  • Phytotherapy
  • Plant Extracts - pharmacology
  • Plant Extracts - therapeutic use
  • Rhodamine 123 - metabolism
  • RNA, Messenger - metabolism
  • Sanguinarine
  • Terpenes - pharmacology
  • Terpenes - therapeutic use
  • β-Carotene
ispartof: Phytomedicine (Stuttgart), 2013-12-15, Vol.21 (1), p.47-61
description: 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
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0944-7113
fulltext: fulltext
issn:
  • 0944-7113
  • 1618-095X
url: Link


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titleInfluence of combinations of digitonin with selected phenolics, terpenoids, and alkaloids on the expression and activity of P-glycoprotein in leukaemia and colon cancer cells
sourceAlma/SFX Local Collection
creatorEid, Safaa Yehia ; El-Readi, Mahmoud Zaki ; Eldin, Essam Eldin Mohamed Nour ; Fatani, Sameer Hassan ; Wink, Michael
creatorcontribEid, Safaa Yehia ; El-Readi, Mahmoud Zaki ; Eldin, Essam Eldin Mohamed Nour ; Fatani, Sameer Hassan ; Wink, Michael
descriptionP-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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1EISSN: 1618-095X
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3PMID: 23999162
languageeng
publisherGermany: Elsevier GmbH
subjectAlkaloids ; Alkaloids - pharmacology ; Alkaloids - therapeutic use ; Antineoplastic Agents, Phytogenic - pharmacology ; Antineoplastic Agents, Phytogenic - therapeutic use ; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics ; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism ; Benzophenanthridines - pharmacology ; Benzophenanthridines - therapeutic use ; beta Carotene - pharmacology ; beta Carotene - therapeutic use ; Caco-2 Cells ; Cancer cells ; Colon cancer ; Colon cells ; Colonic Neoplasms - drug therapy ; Colonic Neoplasms - genetics ; Colonic Neoplasms - metabolism ; Digitonin ; Digitonin - pharmacology ; Digitonin - therapeutic use ; Dose-Response Relationship, Drug ; Drug Combinations ; Drug Resistance, Multiple - drug effects ; Drug Resistance, Neoplasm - drug effects ; Drug Synergism ; Drug therapy ; Drug therapy, Combination ; Fluoresceins - metabolism ; Health aspects ; Humans ; Isoquinolines - pharmacology ; Isoquinolines - therapeutic use ; Leukaemia ; Leukemia - drug therapy ; Leukemia - genetics ; Leukemia - metabolism ; Multidrug resistance ; Phenols - pharmacology ; Phenols - therapeutic use ; Physiological aspects ; Phytochemicals - pharmacology ; Phytochemicals - therapeutic use ; Phytotherapy ; Plant Extracts - pharmacology ; Plant Extracts - therapeutic use ; Rhodamine 123 - metabolism ; RNA, Messenger - metabolism ; Sanguinarine ; Terpenes - pharmacology ; Terpenes - therapeutic use ; β-Carotene
ispartofPhytomedicine (Stuttgart), 2013-12-15, Vol.21 (1), p.47-61
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2COPYRIGHT 2013 Urban & Fischer Verlag
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1El-Readi, Mahmoud Zaki
2Eldin, Essam Eldin Mohamed Nour
3Fatani, Sameer Hassan
4Wink, Michael
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0Influence of combinations of digitonin with selected phenolics, terpenoids, and alkaloids on the expression and activity of P-glycoprotein in leukaemia and colon cancer cells
1Phytomedicine (Stuttgart)
addtitlePhytomedicine
descriptionP-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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0Alkaloids
1Alkaloids - pharmacology
2Alkaloids - therapeutic use
3Antineoplastic Agents, Phytogenic - pharmacology
4Antineoplastic Agents, Phytogenic - therapeutic use
5ATP-Binding Cassette, Sub-Family B, Member 1 - genetics
6ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism
7Benzophenanthridines - pharmacology
8Benzophenanthridines - therapeutic use
9beta Carotene - pharmacology
10beta Carotene - therapeutic use
11Caco-2 Cells
12Cancer cells
13Colon cancer
14Colon cells
15Colonic Neoplasms - drug therapy
16Colonic Neoplasms - genetics
17Colonic Neoplasms - metabolism
18Digitonin
19Digitonin - pharmacology
20Digitonin - therapeutic use
21Dose-Response Relationship, Drug
22Drug Combinations
23Drug Resistance, Multiple - drug effects
24Drug Resistance, Neoplasm - drug effects
25Drug Synergism
26Drug therapy
27Drug therapy, Combination
28Fluoresceins - metabolism
29Health aspects
30Humans
31Isoquinolines - pharmacology
32Isoquinolines - therapeutic use
33Leukaemia
34Leukemia - drug therapy
35Leukemia - genetics
36Leukemia - metabolism
37Multidrug resistance
38Phenols - pharmacology
39Phenols - therapeutic use
40Physiological aspects
41Phytochemicals - pharmacology
42Phytochemicals - therapeutic use
43Phytotherapy
44Plant Extracts - pharmacology
45Plant Extracts - therapeutic use
46Rhodamine 123 - metabolism
47RNA, Messenger - metabolism
48Sanguinarine
49Terpenes - pharmacology
50Terpenes - therapeutic use
51β-Carotene
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titleInfluence of combinations of digitonin with selected phenolics, terpenoids, and alkaloids on the expression and activity of P-glycoprotein in leukaemia and colon cancer cells
authorEid, Safaa Yehia ; El-Readi, Mahmoud Zaki ; Eldin, Essam Eldin Mohamed Nour ; Fatani, Sameer Hassan ; Wink, Michael
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1Alkaloids - pharmacology
2Alkaloids - therapeutic use
3Antineoplastic Agents, Phytogenic - pharmacology
4Antineoplastic Agents, Phytogenic - therapeutic use
5ATP-Binding Cassette, Sub-Family B, Member 1 - genetics
6ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism
7Benzophenanthridines - pharmacology
8Benzophenanthridines - therapeutic use
9beta Carotene - pharmacology
10beta Carotene - therapeutic use
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12Cancer cells
13Colon cancer
14Colon cells
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16Colonic Neoplasms - genetics
17Colonic Neoplasms - metabolism
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20Digitonin - therapeutic use
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22Drug Combinations
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24Drug Resistance, Neoplasm - drug effects
25Drug Synergism
26Drug therapy
27Drug therapy, Combination
28Fluoresceins - metabolism
29Health aspects
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31Isoquinolines - pharmacology
32Isoquinolines - therapeutic use
33Leukaemia
34Leukemia - drug therapy
35Leukemia - genetics
36Leukemia - metabolism
37Multidrug resistance
38Phenols - pharmacology
39Phenols - therapeutic use
40Physiological aspects
41Phytochemicals - pharmacology
42Phytochemicals - therapeutic use
43Phytotherapy
44Plant Extracts - pharmacology
45Plant Extracts - therapeutic use
46Rhodamine 123 - metabolism
47RNA, Messenger - metabolism
48Sanguinarine
49Terpenes - pharmacology
50Terpenes - therapeutic use
51β-Carotene
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jtitlePhytomedicine (Stuttgart)
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date2013-12-15
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volume21
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issn0944-7113
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abstractP-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.
copGermany
pubElsevier GmbH
pmid23999162
doi10.1016/j.phymed.2013.07.019
tpages15