Isopetasin and S-isopetasin as novel P-glycoprotein inhibitors against multidrug-resistant cancer cells

Publication type:
Journal article
Metadata:
Autoren
  • Sara Abdelfatah
  • Madeleine Boeckers
  • Maitane Asensio
  • Onat Kadioglu
  • Anette Klinger
  • Edmond Fleischer
  • Thomas Efferth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000652024800006&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.phymed.2020.153196
eISSN
1618-095X
Externe Identifier
  • Clarivate Analytics Document Solution ID: SE4DZ
  • PubMed Identifier: 32229058
ISSN
0944-7113
Zeitschrift
PHYTOMEDICINE
Schlüsselwörter
  • ABC-transporter
  • Multidrug-resistance
  • Natural products
  • Petasites formosanus
  • P-glycoprotein
Artikelnummer
ARTN 153196
Datum der Veröffentlichung
2021
Status
Published
Titel
Isopetasin and S-isopetasin as novel P-glycoprotein inhibitors against multidrug-resistant cancer cells
Sub types
  • Article
Ausgabe der Zeitschrift
86

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • Sara Abdelfatah
  • Madeleine Böckers
  • Maitane Asensio
  • Onat Kadioglu
  • Anette Klinger
  • Edmond Fleischer
  • Thomas Efferth
DOI
10.1016/j.phymed.2020.153196
ISSN
0944-7113
Zeitschrift
Phytomedicine
Sprache
en
Artikelnummer
153196
Paginierung
153196 - 153196
Datum der Veröffentlichung
2021
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.phymed.2020.153196
Datum der Datenerfassung
2021
Titel
Isopetasin and S-isopetasin as novel P-glycoprotein inhibitors against multidrug-resistant cancer cells
Ausgabe der Zeitschrift
86

Data source: Crossref

Abstract
<h4>Background</h4>A major problem of cancer treatment is the development of multidrug resistance (MDR) to chemotherapy. MDR is caused by different mechanisms such as the expression of the ABC-transporters P-glycoprotein (P-gp, MDR1, ABCB1) and breast cancer resistance protein (BCRP, ABCG2). These transporters efflux xenobiotic toxins, including chemotherapeutics, and they were found to be overexpressed in different cancer types.<h4>Purpose</h4>Identification of novel molecules that overcome MDR by targeting ABC-transporters.<h4>Methods</h4>Resazurin reduction assay was used for cytotoxicity test. AutoDock 4.2. was used for molecular docking. The function of P-gp and BCRP was tested using a doxorubicin uptake assay and an ATPase assay. ROS generation was detected using flow cytometry for the measurement of H<sub>2</sub>DCFH-DA fluorescence. Annexin/PI staining was applied for the detection of apoptosis. Bioinformatic analyses were performed using LigandScout 3.12. software and DataWarrior software.<h4>Results</h4>In our search for new molecules that selectively act against resistant phenotypes, we identified isopetasin and S-isopetasin, which are bioactive natural products from Petasites formosanus. They exerted collateral sensitivity towards leukemia cells with high P-gp expression in CEM/ADR5000 cells, compared to sensitive wild-type CCRF-CEM leukemia cells. Also, they revealed considerable activity towards breast cancer cells overexpressing breast cancer resistance protein, MDA-MB-231-BCRP clone 23. This motivated us to investigate whether the function of P-gp was inhibited. In-silico results showed the compounds bound with high affinity and interacted with key amino acid residues in P-gp . Then, we found that the two compounds increased doxorubicin accumulation in P-gp overexpressing CEM/ADR5000 by three-fold compared to cells without inhibitor. P-gp-mediated drug efflux was ATP-dependent. Isopetasin and S-isopetasin increased the ATPase activity of human P-gp in a comparable fashion as verapamil used as control P-gp inhibitor. As isopetasin and S-isopetasin exerted dual roles, first as cytotoxic compounds and then as P-gp inhibitors, we suggested that their P-gp inhibition is part of a larger complex of mechanisms to induce cell death in cancer patients. P-gp dysfunction induces mitochondrial stress to generate ATP. Upon continuing stress by P-gp inhibition, the mitochondria generate reactive oxygen species (ROS). Initially established for verapamil, this theory was validated in the present study for isopetasin and S-isopetasin, as treatment with the two candidates increased ROS levels in CEM/ADR5000 cells followed by apoptosis.<h4>Conclusion</h4>Our study highlights the importance of isopetasin and S-isopetasin as novel ROS-generating and apoptosis-inducing P-gp inhibitors.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany.
Autoren
  • Sara Abdelfatah
  • Madeleine Böckers
  • Maitane Asensio
  • Onat Kadioglu
  • Anette Klinger
  • Edmond Fleischer
  • Thomas Efferth
DOI
10.1016/j.phymed.2020.153196
eISSN
1618-095X
Externe Identifier
  • PubMed Identifier: 32229058
Funding acknowledgements
  • Deutsche Forschungsgemeinschaft: GRK 2015/2
  • Ministerio de Educación, Cultura y Deporte: GRK 2015/2
  • Ministerio de Educación, Cultura y Deporte: BOE-A-2015-9456
  • Deutsche Forschungsgemeinschaft: BOE-A-2015-9456
Open access
false
ISSN
0944-7113
Zeitschrift
Phytomedicine : international journal of phytotherapy and phytopharmacology
Schlüsselwörter
  • Cell Line, Tumor
  • Humans
  • Sesquiterpenes
  • Neoplasm Proteins
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Molecular Docking Simulation
  • ATP Binding Cassette Transporter, Subfamily B
Sprache
eng
Medium
Print-Electronic
Online publication date
2020
Paginierung
153196
Datum der Veröffentlichung
2021
Status
Published
Datum der Datenerfassung
2020
Titel
Isopetasin and S-isopetasin as novel P-glycoprotein inhibitors against multidrug-resistant cancer cells.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
86

Data source: Europe PubMed Central

Abstract
BACKGROUND: A major problem of cancer treatment is the development of multidrug resistance (MDR) to chemotherapy. MDR is caused by different mechanisms such as the expression of the ABC-transporters P-glycoprotein (P-gp, MDR1, ABCB1) and breast cancer resistance protein (BCRP, ABCG2). These transporters efflux xenobiotic toxins, including chemotherapeutics, and they were found to be overexpressed in different cancer types. PURPOSE: Identification of novel molecules that overcome MDR by targeting ABC-transporters. METHODS: Resazurin reduction assay was used for cytotoxicity test. AutoDock 4.2. was used for molecular docking. The function of P-gp and BCRP was tested using a doxorubicin uptake assay and an ATPase assay. ROS generation was detected using flow cytometry for the measurement of H2DCFH-DA fluorescence. Annexin/PI staining was applied for the detection of apoptosis. Bioinformatic analyses were performed using LigandScout 3.12. software and DataWarrior software. RESULTS: In our search for new molecules that selectively act against resistant phenotypes, we identified isopetasin and S-isopetasin, which are bioactive natural products from Petasites formosanus. They exerted collateral sensitivity towards leukemia cells with high P-gp expression in CEM/ADR5000 cells, compared to sensitive wild-type CCRF-CEM leukemia cells. Also, they revealed considerable activity towards breast cancer cells overexpressing breast cancer resistance protein, MDA-MB-231-BCRP clone 23. This motivated us to investigate whether the function of P-gp was inhibited. In-silico results showed the compounds bound with high affinity and interacted with key amino acid residues in P-gp . Then, we found that the two compounds increased doxorubicin accumulation in P-gp overexpressing CEM/ADR5000 by three-fold compared to cells without inhibitor. P-gp-mediated drug efflux was ATP-dependent. Isopetasin and S-isopetasin increased the ATPase activity of human P-gp in a comparable fashion as verapamil used as control P-gp inhibitor. As isopetasin and S-isopetasin exerted dual roles, first as cytotoxic compounds and then as P-gp inhibitors, we suggested that their P-gp inhibition is part of a larger complex of mechanisms to induce cell death in cancer patients. P-gp dysfunction induces mitochondrial stress to generate ATP. Upon continuing stress by P-gp inhibition, the mitochondria generate reactive oxygen species (ROS). Initially established for verapamil, this theory was validated in the present study for isopetasin and S-isopetasin, as treatment with the two candidates increased ROS levels in CEM/ADR5000 cells followed by apoptosis. CONCLUSION: Our study highlights the importance of isopetasin and S-isopetasin as novel ROS-generating and apoptosis-inducing P-gp inhibitors.
Date of acceptance
2020
Autoren
  • Sara Abdelfatah
  • Madeleine Böckers
  • Maitane Asensio
  • Onat Kadioglu
  • Anette Klinger
  • Edmond Fleischer
  • Thomas Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/32229058
DOI
10.1016/j.phymed.2020.153196
eISSN
1618-095X
Zeitschrift
Phytomedicine
Schlüsselwörter
  • ABC-transporter
  • Multidrug-resistance
  • Natural products
  • P-glycoprotein
  • Petasites formosanus
  • ATP Binding Cassette Transporter, Subfamily B
  • Cell Line, Tumor
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Humans
  • Molecular Docking Simulation
  • Neoplasm Proteins
  • Sesquiterpenes
Sprache
eng
Country
Germany
Paginierung
153196
PII
S0944-7113(20)30029-5
Datum der Veröffentlichung
2021
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2021
Titel
Isopetasin and S-isopetasin as novel P-glycoprotein inhibitors against multidrug-resistant cancer cells.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
86

Data source: PubMed

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