Reversal of multidrug resistance by Marsdenia tenacissima and its main active ingredients polyoxypregnanes

Publication type:
Journal article
Metadata:
Autoren
  • Kenneth KW To
  • Xu Wu
  • Chun Yin
  • Stella Chai
  • Sheng Yao
  • Onat Kadioglu
  • Thomas Efferth
  • Yang Ye
  • Ge Lin
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000401214700012&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.jep.2017.03.051
Externe Identifier
  • Clarivate Analytics Document Solution ID: EU7KW
  • PubMed Identifier: 28363522
ISSN
0378-8741
Zeitschrift
JOURNAL OF ETHNOPHARMACOLOGY
Schlüsselwörter
  • ABCG2
  • Multidrug resistance
  • Marsdenia tenacissima
  • MRP1
  • P-glycoprotein
  • Polyoxypregnane compounds
Paginierung
110 - 119
Datum der Veröffentlichung
2017
Status
Published
Titel
Reversal of multidrug resistance by <i>Marsdenia tenacissima</i> and its main active ingredients polyoxypregnanes
Sub types
  • Article
Ausgabe der Zeitschrift
203

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • Kenneth KW To
  • Xu Wu
  • Chun Yin
  • Stella Chai
  • Sheng Yao
  • Onat Kadioglu
  • Thomas Efferth
  • Yang Ye
  • Ge Lin
DOI
10.1016/j.jep.2017.03.051
ISSN
0378-8741
Zeitschrift
Journal of Ethnopharmacology
Sprache
en
Paginierung
110 - 119
Datum der Veröffentlichung
2017
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.jep.2017.03.051
Datum der Datenerfassung
2022
Titel
Reversal of multidrug resistance by Marsdenia tenacissima and its main active ingredients polyoxypregnanes
Ausgabe der Zeitschrift
203

Data source: Crossref

Abstract
<h4>Ethnopharmacological relevance</h4>Multidrug resistance (MDR) of cancer is often associated with the overexpression of ATP-binding cassette (ABC) transporters, such as P-glycoprotein (P-gp), multidrug resistance-associated protein-1 (MRP-1) and breast cancer resistance protein (BCRP or ABCG2), in cancer cells, which facilitates the active efflux of a wide variety of chemotherapeutic drugs out of the cells. Marsdenia tenacissima is a traditional Chinese medicinal herb that has long been clinically used for treatment of cancers, particularly in combinational use with anticancer drugs. Polyoxypregnanes (POPs) are identified as main constituents of this herb, and three of them have been reported to exhibit P-gp modulatory effect and thus reverse MDR. Therefore, it is of great necessity to investigate more POPs that have potential to reverse transporters-mediated MDR.<h4>Aim of the study</h4>We aimed to identify POPs as the chemical basis responsible for circumventing ABC transporters-mediated MDR by M. tenacissima.<h4>Materials and methods</h4>The MDR reversal effects of M. tenacissima crude extract together with a series of isolated POPs were evaluated on several MDR cancer cell lines that overexpress P-gp, MRP1 or ABCG2. The activities of P-gp, MRP1 and ABCG2 were determined by the flow cytometry-based substrate efflux assay. Molecular docking of POPs to a three-dimensional human P-gp homology structure was also performed.<h4>Results</h4>The crude extract of M. tenacissima was firstly found to circumvent P-gp-mediated MDR. Then, 11 polyoxypregnane compounds (POPs) isolated from this herb were found to overcome P-gp-, MRP1- and/or ABCG2-mediated MDR. Further mechanistic study delineated that the reversal of MDR by these POPs was due to significant increase in the intracellular concentrations of the substrate anticancer drugs via their inhibition of different ABC transporter-mediated efflux activities. Furthermore, molecular docking revealed that POPs with P-gp modulatory effect bound to P-gp and fitted well into the cavity between the alpha and beta subunit of P-gp via forming hydrogen bonds. In addition, several key structural determinants for inhibition of P-gp, MRP1 or ABCG2 by POPs were illustrated.<h4>Conclusions</h4>Our findings advocated the rational use of M. tenacissima to enhance efficacies of conventional anticancer drugs in tumors with ABC drug transporters-mediated MDR. Furthermore, 11 POPs were found to contribute to MDR reversal effect of M. tenacissima via inhibition of different ABC efflux transporters.
Addresses
  • School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Joint Research Laboratory of Promoting Globalization of Traditional Chinese Medicines between The Chinese University of Hong Kong and Shanghai Institute of Materia Medica, Chinese Academy of Sciences, PR China.
Autoren
  • Kenneth KW To
  • Xu Wu
  • Chun Yin
  • Stella Chai
  • Sheng Yao
  • Onat Kadioglu
  • Thomas Efferth
  • Thomas Efferth
  • Yang Ye
  • Ge Lin
DOI
10.1016/j.jep.2017.03.051
eISSN
1872-7573
Externe Identifier
  • PubMed Identifier: 28363522
Funding acknowledgements
  • CUHK: 3132968
  • Health and Medical Research Fund: 08090481
  • Chinese University of Hong Kong: 2041448
Open access
false
ISSN
0378-8741
Zeitschrift
Journal of ethnopharmacology
Schlüsselwörter
  • Cell Line, Tumor
  • Humans
  • Marsdenia
  • Neoplasms
  • Pregnanes
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Plant Extracts
  • Antineoplastic Agents
  • Flow Cytometry
  • Drug Resistance, Multiple
  • Gene Expression Regulation, Neoplastic
  • Drug Resistance, Neoplasm
  • Molecular Docking Simulation
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
Sprache
eng
Medium
Print-Electronic
Online publication date
2017
Paginierung
110 - 119
Datum der Veröffentlichung
2017
Status
Published
Datum der Datenerfassung
2017
Titel
Reversal of multidrug resistance by Marsdenia tenacissima and its main active ingredients polyoxypregnanes.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
203

Data source: Europe PubMed Central

Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Multidrug resistance (MDR) of cancer is often associated with the overexpression of ATP-binding cassette (ABC) transporters, such as P-glycoprotein (P-gp), multidrug resistance-associated protein-1 (MRP-1) and breast cancer resistance protein (BCRP or ABCG2), in cancer cells, which facilitates the active efflux of a wide variety of chemotherapeutic drugs out of the cells. Marsdenia tenacissima is a traditional Chinese medicinal herb that has long been clinically used for treatment of cancers, particularly in combinational use with anticancer drugs. Polyoxypregnanes (POPs) are identified as main constituents of this herb, and three of them have been reported to exhibit P-gp modulatory effect and thus reverse MDR. Therefore, it is of great necessity to investigate more POPs that have potential to reverse transporters-mediated MDR. AIM OF THE STUDY: We aimed to identify POPs as the chemical basis responsible for circumventing ABC transporters-mediated MDR by M. tenacissima. MATERIALS AND METHODS: The MDR reversal effects of M. tenacissima crude extract together with a series of isolated POPs were evaluated on several MDR cancer cell lines that overexpress P-gp, MRP1 or ABCG2. The activities of P-gp, MRP1 and ABCG2 were determined by the flow cytometry-based substrate efflux assay. Molecular docking of POPs to a three-dimensional human P-gp homology structure was also performed. RESULTS: The crude extract of M. tenacissima was firstly found to circumvent P-gp-mediated MDR. Then, 11 polyoxypregnane compounds (POPs) isolated from this herb were found to overcome P-gp-, MRP1- and/or ABCG2-mediated MDR. Further mechanistic study delineated that the reversal of MDR by these POPs was due to significant increase in the intracellular concentrations of the substrate anticancer drugs via their inhibition of different ABC transporter-mediated efflux activities. Furthermore, molecular docking revealed that POPs with P-gp modulatory effect bound to P-gp and fitted well into the cavity between the alpha and beta subunit of P-gp via forming hydrogen bonds. In addition, several key structural determinants for inhibition of P-gp, MRP1 or ABCG2 by POPs were illustrated. CONCLUSIONS: Our findings advocated the rational use of M. tenacissima to enhance efficacies of conventional anticancer drugs in tumors with ABC drug transporters-mediated MDR. Furthermore, 11 POPs were found to contribute to MDR reversal effect of M. tenacissima via inhibition of different ABC efflux transporters.
Autoren
  • Kenneth KW To
  • Xu Wu
  • Chun Yin
  • Stella Chai
  • Sheng Yao
  • Onat Kadioglu
  • Thomas Efferth
  • Yang Ye
  • Ge Lin
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/28363522
DOI
10.1016/j.jep.2017.03.051
eISSN
1872-7573
Zeitschrift
J Ethnopharmacol
Schlüsselwörter
  • ABCG2
  • Calcein AM (PubChem CID390986)
  • Doxorubicin (PubChem CID31703)
  • Fumitremorgin C (PubChem CID403923)
  • MK571(PubChem CID16760569)
  • MRP1
  • Marsdenia tenacissima
  • Mitoxantrone (PubChem CID4212)
  • Multidrug resistance
  • P-glycoprotein
  • Pheophorbide A (PubChem CID5323510)
  • Polyoxypregnane compounds
  • Rhodamine 123 (PubChem CID65217)
  • Sulforhodamine B (PubChem CID65191)
  • Valspodar (PubChem CID5281884)
  • Verapamil (PubChem CID2520)
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Antineoplastic Agents
  • Cell Line, Tumor
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Marsdenia
  • Molecular Docking Simulation
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Neoplasms
  • Plant Extracts
  • Pregnanes
Sprache
eng
Country
Ireland
Paginierung
110 - 119
PII
S0378-8741(16)31342-3
Datum der Veröffentlichung
2017
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2018
Titel
Reversal of multidrug resistance by Marsdenia tenacissima and its main active ingredients polyoxypregnanes.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
203

Data source: PubMed

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