Collateral Sensitivity of Parthenolide via NF-κB and HIF-α Inhibition and Epigenetic Changes in Drug-Resistant Cancer Cell Lines

Publication type:
Journal article
Metadata:
Autoren
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000468411600001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.3389/fphar.2019.00542
Externe Identifier
  • Clarivate Analytics Document Solution ID: HY8SV
  • PubMed Identifier: 31164821
ISSN
1663-9812
Zeitschrift
FRONTIERS IN PHARMACOLOGY
Schlüsselwörter
  • drug resistance
  • chemotherapy
  • HDAC
  • natural products
  • NF-kappa B
  • pharmacogenomics
  • phytochemicals
Artikelnummer
ARTN 542
Datum der Veröffentlichung
2019
Status
Published
Titel
Collateral Sensitivity of Parthenolide via NF-κB and HIF-α Inhibition and Epigenetic Changes in Drug-Resistant Cancer Cell Lines
Sub types
  • Article
Ausgabe der Zeitschrift
10

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
DOI
10.3389/fphar.2019.00542
eISSN
1663-9812
Zeitschrift
Frontiers in Pharmacology
Online publication date
2019
Status
Published online
Herausgeber
Frontiers Media SA
Herausgeber URL
http://dx.doi.org/10.3389/fphar.2019.00542
Datum der Datenerfassung
2023
Titel
Collateral Sensitivity of Parthenolide via NF-κB and HIF-α Inhibition and Epigenetic Changes in Drug-Resistant Cancer Cell Lines
Ausgabe der Zeitschrift
10

Data source: Crossref

Abstract
Parthenolide (PT) is a sesquiterpene lactone isolated from <i>Tanacetum parthenium</i>. In this study, PT showed varying cytotoxic effects against different solid tumor cell lines. HCT116 (p53<sup>+/+</sup>) colon carcinoma cells and their parental HCT116 knockout p53 (p53<sup>-/-</sup>) cell lines showed a resistance degree of 2.36. On the other hand, wild-type U87.MG cells or cells transfected with a deletion-activated <i>EGFR</i> cDNA (U87.MGΔEGFR) exhibited slight sensitivity toward PT. Multidrug-resistant MDA-MB-231-BCRP cells were even more sensitive toward PT than sensitive MDA-MB-231-pcDNA cells with a resistance degree of 0.07 (collateral sensitivity). To the best of our knowledge, hypersensitivity (collateral sensitivity) in MDA-MB-231-BCRP cell line is reported in this study for the first time. We attempted to identify the mechanism of collateral sensitivity. Firstly, we found that PT bound to IKK preventing IκBα degradation and eventually inhibition of the nuclear factor kappa B (NF-κB) pathway. Down-regulation of hypoxia inducing factor 1-alpha (HIF-1α) in MDA-MB-231-BCRP resistant cells may be a second mechanism, since it is a target gene of NF-κB. Moreover, PT also showed epigenetic effect by inhibition of HDAC activity as shown using both molecular docking and HDAC activity assay. Based on COMPARE and hierarchical cluster analyses, we found gene expression profiles that predicted sensitivity or resistance of 47 tumor cell lines toward PT. Interestingly, pathway analyses of gene expression profiles revealed NF-κB and HIF signaling as top networks of these genes, cellular functions and canonical pathways influencing the activity of PT against tumor cells. In conclusion, PT exerted profound cytotoxic activity against various cancer cell lines mainly against BCRP-overexpressing tumor cells, suggesting PT as novel candidate for cancer treatment.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
Autoren
DOI
10.3389/fphar.2019.00542
eISSN
1663-9812
Externe Identifier
  • PubMed Identifier: 31164821
  • PubMed Central ID: PMC6536578
Open access
true
ISSN
1663-9812
Zeitschrift
Frontiers in pharmacology
Sprache
eng
Medium
Electronic-eCollection
Online publication date
2019
Open access status
Open Access
Paginierung
542
Datum der Veröffentlichung
2019
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
2019
Titel
Collateral Sensitivity of Parthenolide via NF-κB and HIF-α Inhibition and Epigenetic Changes in Drug-Resistant Cancer Cell Lines.
Sub types
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
10

Files

https://www.frontiersin.org/articles/10.3389/fphar.2019.00542/pdf https://europepmc.org/articles/PMC6536578?pdf=render

Data source: Europe PubMed Central

Abstract
Parthenolide (PT) is a sesquiterpene lactone isolated from Tanacetum parthenium. In this study, PT showed varying cytotoxic effects against different solid tumor cell lines. HCT116 (p53+/+) colon carcinoma cells and their parental HCT116 knockout p53 (p53-/-) cell lines showed a resistance degree of 2.36. On the other hand, wild-type U87.MG cells or cells transfected with a deletion-activated EGFR cDNA (U87.MGΔEGFR) exhibited slight sensitivity toward PT. Multidrug-resistant MDA-MB-231-BCRP cells were even more sensitive toward PT than sensitive MDA-MB-231-pcDNA cells with a resistance degree of 0.07 (collateral sensitivity). To the best of our knowledge, hypersensitivity (collateral sensitivity) in MDA-MB-231-BCRP cell line is reported in this study for the first time. We attempted to identify the mechanism of collateral sensitivity. Firstly, we found that PT bound to IKK preventing IκBα degradation and eventually inhibition of the nuclear factor kappa B (NF-κB) pathway. Down-regulation of hypoxia inducing factor 1-alpha (HIF-1α) in MDA-MB-231-BCRP resistant cells may be a second mechanism, since it is a target gene of NF-κB. Moreover, PT also showed epigenetic effect by inhibition of HDAC activity as shown using both molecular docking and HDAC activity assay. Based on COMPARE and hierarchical cluster analyses, we found gene expression profiles that predicted sensitivity or resistance of 47 tumor cell lines toward PT. Interestingly, pathway analyses of gene expression profiles revealed NF-κB and HIF signaling as top networks of these genes, cellular functions and canonical pathways influencing the activity of PT against tumor cells. In conclusion, PT exerted profound cytotoxic activity against various cancer cell lines mainly against BCRP-overexpressing tumor cells, suggesting PT as novel candidate for cancer treatment.
Date of acceptance
2019
Autoren
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/31164821
DOI
10.3389/fphar.2019.00542
Externe Identifier
  • PubMed Central ID: PMC6536578
ISSN
1663-9812
Zeitschrift
Front Pharmacol
Schlüsselwörter
  • HDAC
  • NF-κB
  • chemotherapy
  • drug resistance
  • natural products
  • pharmacogenomics
  • phytochemicals
Sprache
eng
Country
Switzerland
Paginierung
542
Datum der Veröffentlichung
2019
Status
Published online
Titel
Collateral Sensitivity of Parthenolide via NF-κB and HIF-α Inhibition and Epigenetic Changes in Drug-Resistant Cancer Cell Lines.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
10

Data source: PubMed

Author's licence
CC-BY
Autoren
Hosting institution
Universitätsbibliothek Mainz
Sammlungen
  • JGU-Publikationen
Resource version
Published version
URN
urn:nbn:de:hebis:77-publ-591017
DOI
10.3389/fphar.2019.00542
Funding acknowledgements
  • DFG, Open Access-Publizieren Universität Mainz / Universitätsmedizin
File(s) embargoed
false
Open access
true
ISSN
1663-9812
Zeitschrift
Frontiers in pharmacology
Schlüsselwörter
  • 570 Biowissenschaften
  • 570 Life sciences
Sprache
eng
Open access status
Open Access
Paginierung
Art. 542
Datum der Veröffentlichung
2019
Public URL
https://openscience.ub.uni-mainz.de/handle/20.500.12030/153
Herausgeber
Frontiers Media
Herausgeber URL
http://dx.doi.org/10.3389/fphar.2019.00542
Datum der Datenerfassung
2019
Datum, an dem der Datensatz öffentlich gemacht wurde
2019
Zugang
Public
Titel
Collateral sensitivity of parthenolide via NF-κB and HIF-α inhibition and epigenetic changes in drug-resistant cancer cell lines
Ausgabe der Zeitschrift
10

Files

dawood_mona-collateral_sen-20200928110332836.pdf

Data source: OPENSCIENCE.UB

Beziehungen:
Property of

Tools