Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy in vitro and in vivo

Publication type:
Journal article
Metadata:
Autoren
  • Xu Wu
  • Chun Yin
  • Jiang Ma
  • Stella Chai
  • Chunyuan Zhang
  • Sheng Yao
  • Onat Kadioglu
  • Thomas Efferth
  • Yang Ye
  • Kenneth Kin-Wah To
  • Ge Lin
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000677639400011&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.apsb.2020.12.021
eISSN
2211-3843
Externe Identifier
  • Clarivate Analytics Document Solution ID: TP5KY
  • PubMed Identifier: 34386326
ISSN
2211-3835
Ausgabe der Veröffentlichung
7
Zeitschrift
ACTA PHARMACEUTICA SINICA B
Schlüsselwörter
  • Multidrug resistance
  • ABCB1
  • Polyoxypregnane
  • Combination chemotherapy
  • Marsdenia tenacissima
Paginierung
1885 - 1902
Datum der Veröffentlichung
2021
Status
Published
Titel
Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy <i>in vitro</i> and <i>in vivo</i>
Sub types
  • Article
Ausgabe der Zeitschrift
11

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • Xu Wu
  • Chun Yin
  • Jiang Ma
  • Stella Chai
  • Chunyuan Zhang
  • Sheng Yao
  • Onat Kadioglu
  • Thomas Efferth
  • Yang Ye
  • Kenneth Kin-Wah To
  • Ge Lin
DOI
10.1016/j.apsb.2020.12.021
ISSN
2211-3835
Ausgabe der Veröffentlichung
7
Zeitschrift
Acta Pharmaceutica Sinica B
Sprache
en
Paginierung
1885 - 1902
Datum der Veröffentlichung
2021
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.apsb.2020.12.021
Datum der Datenerfassung
2023
Titel
Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy in vitro and in vivo
Ausgabe der Zeitschrift
11

Data source: Crossref

Abstract
Multidrug resistance (MDR) mediated by ATP binding cassette subfamily B member 1 (ABCB1) is significantly hindering effective cancer chemotherapy. However, currently, no ABCB1-inhibitory drugs have been approved to treat MDR cancer clinically, mainly due to the inhibitor specificity, toxicity, and drug interactions. Here, we reported that three polyoxypregnanes (POPs) as the most abundant constituents of <i>Marsdenia tenacissima</i> (<i>M. tenacissima</i>) were novel ABCB1-modulatory pro-drugs, which underwent intestinal microbiota-mediated biotransformation <i>in vivo</i> to generate active metabolites. The metabolites at non-toxic concentrations restored chemosensitivity in ABCB1-overexpressing cancer cells <i>via</i> inhibiting ABCB1 efflux activity without changing ABCB1 protein expression, which were further identified as specific non-competitive inhibitors of ABCB1 showing multiple binding sites within ABCB1 drug cavity. These POPs did not exhibit ABCB1/drug metabolizing enzymes interplay, and their repeated administration generated predictable pharmacokinetic interaction with paclitaxel without obvious toxicity <i>in vivo</i>. We further showed that these POPs enhanced the accumulation of paclitaxel in tumors and overcame ABCB1-mediated chemoresistance. The results suggested that these POPs had the potential to be developed as safe, potent, and specific pro-drugs to reverse ABCB1-mediated MDR. Our work also provided scientific evidence for the use of <i>M. tenacissima</i> in combinational chemotherapy.
Addresses
  • School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong 999077, China.
Autoren
  • Xu Wu
  • Chun Yin
  • Jiang Ma
  • Stella Chai
  • Chunyuan Zhang
  • Sheng Yao
  • Onat Kadioglu
  • Thomas Efferth
  • Yang Ye
  • Kenneth Kin-Wah To
  • Ge Lin
DOI
10.1016/j.apsb.2020.12.021
eISSN
2211-3843
Externe Identifier
  • PubMed Identifier: 34386326
  • PubMed Central ID: PMC8343194
Open access
true
ISSN
2211-3835
Ausgabe der Veröffentlichung
7
Zeitschrift
Acta pharmaceutica Sinica. B
Sprache
eng
Medium
Print-Electronic
Online publication date
2021
Open access status
Open Access
Paginierung
1885 - 1902
Datum der Veröffentlichung
2021
Status
Published
Publisher licence
CC BY-NC-ND
Datum der Datenerfassung
2021
Titel
Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy <i>in vitro</i> and <i>in vivo</i>.
Sub types
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
11

Files

https://europepmc.org/articles/PMC8343194?pdf=render

Data source: Europe PubMed Central

Abstract
Multidrug resistance (MDR) mediated by ATP binding cassette subfamily B member 1 (ABCB1) is significantly hindering effective cancer chemotherapy. However, currently, no ABCB1-inhibitory drugs have been approved to treat MDR cancer clinically, mainly due to the inhibitor specificity, toxicity, and drug interactions. Here, we reported that three polyoxypregnanes (POPs) as the most abundant constituents of Marsdenia tenacissima (M. tenacissima) were novel ABCB1-modulatory pro-drugs, which underwent intestinal microbiota-mediated biotransformation in vivo to generate active metabolites. The metabolites at non-toxic concentrations restored chemosensitivity in ABCB1-overexpressing cancer cells via inhibiting ABCB1 efflux activity without changing ABCB1 protein expression, which were further identified as specific non-competitive inhibitors of ABCB1 showing multiple binding sites within ABCB1 drug cavity. These POPs did not exhibit ABCB1/drug metabolizing enzymes interplay, and their repeated administration generated predictable pharmacokinetic interaction with paclitaxel without obvious toxicity in vivo. We further showed that these POPs enhanced the accumulation of paclitaxel in tumors and overcame ABCB1-mediated chemoresistance. The results suggested that these POPs had the potential to be developed as safe, potent, and specific pro-drugs to reverse ABCB1-mediated MDR. Our work also provided scientific evidence for the use of M. tenacissima in combinational chemotherapy.
Date of acceptance
2020
Autoren
  • Xu Wu
  • Chun Yin
  • Jiang Ma
  • Stella Chai
  • Chunyuan Zhang
  • Sheng Yao
  • Onat Kadioglu
  • Thomas Efferth
  • Yang Ye
  • Kenneth Kin-Wah To
  • Ge Lin
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/34386326
DOI
10.1016/j.apsb.2020.12.021
Externe Identifier
  • PubMed Central ID: PMC8343194
ISSN
2211-3835
Ausgabe der Veröffentlichung
7
Zeitschrift
Acta Pharm Sin B
Schlüsselwörter
  • ABC, ATP-binding cassette
  • ABCB1
  • ABCB1, ATP binding cassette subfamily B member 1
  • ABCC1, ATP binding cassette subfamily C member 1
  • ABCG2, ATP binding cassette subfamily G member 2
  • ATF3, activating transcription factor 3
  • AUC0–∞, area under plasma concentration vs. time curve
  • BBB, blood–brain barrier
  • BHI, brain heart infusion
  • CL, clearance
  • CYP, cytochrome P450 isozyme
  • Cmax, peak concentration
  • Combination chemotherapy
  • Dox, doxorubicin
  • ECL, electrochemiluminescence
  • EVOM, epithelial tissue voltohmmeter
  • F, bioavailability
  • FBS, fetal bovine serum
  • GAPDH, glyceraldehyde-3-phosphate dehydrogenase
  • H&E, hematoxylin and eosin
  • HBSS, Hankʹs balanced salt solution
  • IC50, half maximal inhibitory concentration
  • LBE, lowest binding energy
  • LC–MS, liquid chromatography coupled with mass spectrometry
  • M. tenacissima, Marsdenia tenacissima
  • MDR, multidrug resistance
  • MDR1a, multidrug resistance protein 1a
  • MRT, mean residence time
  • Marsdenia tenacissima
  • Multidrug resistance
  • N.A., not applicable
  • N.D., not detected
  • NADPH, reduced nicotinamide adenine dinucleotide phosphate
  • NMPA, National Medical Products Administration
  • PBS, phosphate buffer saline
  • PCR, polymerase chain reaction
  • PE, phycoerythrin
  • PI, propidium iodide
  • POP, polyoxypregnane
  • PXR, pregnane X receptor
  • Papp, apparent permeability
  • Polyoxypregnane
  • SD, standard derivation
  • SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis
  • TEER, transepithelial electrical resistance
  • Tmax, time for peak concentration
  • UIC-2, mouse monoclonal ABCB1 antibody
  • Vd, volume of distribution
  • qPCR, quantitative PCR
  • t1/2, elimination half-life
Sprache
eng
Country
Netherlands
Paginierung
1885 - 1902
PII
S2211-3835(21)00003-4
Datum der Veröffentlichung
2021
Status
Published
Titel
Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy in vitro and in vivo.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
11

Data source: PubMed

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