Network pharmacology of triptolide in cancer cells: implications for transcription factor binding

Publication type:
Journal article
Metadata:
Autoren
  • Ean-Jeong Seo
  • Mona Dawood
  • Annika K Hult
  • Martin L Olsson
  • Thomas Efferth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000669172600001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1007/s10637-021-01137-y
eISSN
1573-0646
Externe Identifier
  • Clarivate Analytics Document Solution ID: WL2BX
  • PubMed Identifier: 34213719
ISSN
0167-6997
Ausgabe der Veröffentlichung
6
Zeitschrift
INVESTIGATIONAL NEW DRUGS
Schlüsselwörter
  • Microarrays
  • Natural products
  • Network pharmacology
  • Phytochemicals
  • Precision medicine
Paginierung
1523 - 1537
Datum der Veröffentlichung
2021
Status
Published
Titel
Network pharmacology of triptolide in cancer cells: implications for transcription factor binding
Sub types
  • Article
Ausgabe der Zeitschrift
39

Data source: Web of Science (Lite)

Other metadata sources:
Abstract
<jats:title>Summary</jats:title><jats:p><jats:italic>Background</jats:italic> Triptolide is an active natural product, which inhibits cell proliferation, induces cell apoptosis, suppresses tumor metastasis and improves the effect of other therapeutic treatments in several cancer cell lines by affecting multiple molecules and signaling pathways, such as caspases, heat-shock proteins, DNA damage and NF-ĸB. <jats:italic>Purpose </jats:italic>We investigated the effect of triptolide towards NF-ĸB and GATA1. <jats:italic>Methods </jats:italic>We used cell viability assay, compare and cluster analyses of microarray-based mRNA transcriptome-wide expression data, gene promoter binding motif analysis, molecular docking, Ingenuity pathway analysis, NF-ĸB reporter cell assay, and electrophoretic mobility shift assay (EMSA) of GATA1. <jats:italic>Results </jats:italic>Triptolide inhibited the growth of drug-sensitive (CCRF-CEM, U87.MG) and drug-resistant cell lines (CEM/ADR5000, U87.MGΔEGFR). Hierarchical cluster analysis showed six major clusters in dendrogram. The sensitive and resistant cell lines were statistically significant (<jats:italic>p</jats:italic> = 0.65 × 10<jats:sup>–2</jats:sup>) distributed. The binding motifs of NF-κB (Rel) and of GATA1 proteins were significantly enriched in regions of 25 kb upstream promoter of all genes. IPA showed the networks, biological functions, and canonical pathways influencing the activity of triptolide towards tumor cells. Interestingly, upstream analysis for the 40 genes identified by compare analysis revealed ZFPM1 (friend of GATA protein 1) as top transcription regulator. However, we did not observe any effect of triptolide to the binding of GATA1 in vitro. We confirmed that triptolide inhibited NF-κB activity, and it strongly bound to the pharmacophores of IκB kinase β and NF-κB in silico. <jats:italic>Conclusion </jats:italic>Triptolide showed promising inhibitory effect toward NF-κB, making it a potential candidate for targeting NF-κB.</jats:p>
Autoren
  • Ean-Jeong Seo
  • Mona Dawood
  • Annika K Hult
  • Martin L Olsson
  • Thomas Efferth
DOI
10.1007/s10637-021-01137-y
eISSN
1573-0646
ISSN
0167-6997
Ausgabe der Veröffentlichung
6
Zeitschrift
Investigational New Drugs
Sprache
en
Online publication date
2021
Paginierung
1523 - 1537
Datum der Veröffentlichung
2021
Status
Published
Herausgeber
Springer Science and Business Media LLC
Herausgeber URL
http://dx.doi.org/10.1007/s10637-021-01137-y
Datum der Datenerfassung
2023
Titel
Network pharmacology of triptolide in cancer cells: implications for transcription factor binding
Ausgabe der Zeitschrift
39

Data source: Crossref

Abstract
Background Triptolide is an active natural product, which inhibits cell proliferation, induces cell apoptosis, suppresses tumor metastasis and improves the effect of other therapeutic treatments in several cancer cell lines by affecting multiple molecules and signaling pathways, such as caspases, heat-shock proteins, DNA damage and NF-ĸB. Purpose We investigated the effect of triptolide towards NF-ĸB and GATA1. Methods We used cell viability assay, compare and cluster analyses of microarray-based mRNA transcriptome-wide expression data, gene promoter binding motif analysis, molecular docking, Ingenuity pathway analysis, NF-ĸB reporter cell assay, and electrophoretic mobility shift assay (EMSA) of GATA1. Results Triptolide inhibited the growth of drug-sensitive (CCRF-CEM, U87.MG) and drug-resistant cell lines (CEM/ADR5000, U87.MGΔEGFR). Hierarchical cluster analysis showed six major clusters in dendrogram. The sensitive and resistant cell lines were statistically significant (p = 0.65 × 10<sup>-2</sup>) distributed. The binding motifs of NF-κB (Rel) and of GATA1 proteins were significantly enriched in regions of 25 kb upstream promoter of all genes. IPA showed the networks, biological functions, and canonical pathways influencing the activity of triptolide towards tumor cells. Interestingly, upstream analysis for the 40 genes identified by compare analysis revealed ZFPM1 (friend of GATA protein 1) as top transcription regulator. However, we did not observe any effect of triptolide to the binding of GATA1 in vitro. We confirmed that triptolide inhibited NF-κB activity, and it strongly bound to the pharmacophores of IκB kinase β and NF-κB in silico. Conclusion Triptolide showed promising inhibitory effect toward NF-κB, making it a potential candidate for targeting NF-κB.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128, Mainz, Germany.
Autoren
  • Ean-Jeong Seo
  • Mona Dawood
  • Annika K Hult
  • Martin L Olsson
  • Thomas Efferth
DOI
10.1007/s10637-021-01137-y
eISSN
1573-0646
Externe Identifier
  • PubMed Identifier: 34213719
  • PubMed Central ID: PMC8541937
Funding acknowledgements
  • Johannes Gutenberg-Universität Mainz:
Open access
true
ISSN
0167-6997
Ausgabe der Veröffentlichung
6
Zeitschrift
Investigational new drugs
Schlüsselwörter
  • Cell Line, Tumor
  • Humans
  • Epoxy Compounds
  • Diterpenes
  • Phenanthrenes
  • NF-kappa B
  • Transcription Factors
  • RNA, Messenger
  • Electrophoretic Mobility Shift Assay
  • Cell Survival
  • Protein Binding
  • GATA1 Transcription Factor
  • Molecular Docking Simulation
  • Network Pharmacology
Sprache
eng
Medium
Print-Electronic
Online publication date
2021
Open access status
Open Access
Paginierung
1523 - 1537
Datum der Veröffentlichung
2021
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
2021
Titel
Network pharmacology of triptolide in cancer cells: implications for transcription factor binding.
Sub types
  • Research Support, Non-U.S. Gov't
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
39

Files

https://link.springer.com/content/pdf/10.1007/s10637-021-01137-y.pdf https://europepmc.org/articles/PMC8541937?pdf=render

Data source: Europe PubMed Central

Abstract
Background Triptolide is an active natural product, which inhibits cell proliferation, induces cell apoptosis, suppresses tumor metastasis and improves the effect of other therapeutic treatments in several cancer cell lines by affecting multiple molecules and signaling pathways, such as caspases, heat-shock proteins, DNA damage and NF-ĸB. Purpose We investigated the effect of triptolide towards NF-ĸB and GATA1. Methods We used cell viability assay, compare and cluster analyses of microarray-based mRNA transcriptome-wide expression data, gene promoter binding motif analysis, molecular docking, Ingenuity pathway analysis, NF-ĸB reporter cell assay, and electrophoretic mobility shift assay (EMSA) of GATA1. Results Triptolide inhibited the growth of drug-sensitive (CCRF-CEM, U87.MG) and drug-resistant cell lines (CEM/ADR5000, U87.MGΔEGFR). Hierarchical cluster analysis showed six major clusters in dendrogram. The sensitive and resistant cell lines were statistically significant (p = 0.65 × 10-2) distributed. The binding motifs of NF-κB (Rel) and of GATA1 proteins were significantly enriched in regions of 25 kb upstream promoter of all genes. IPA showed the networks, biological functions, and canonical pathways influencing the activity of triptolide towards tumor cells. Interestingly, upstream analysis for the 40 genes identified by compare analysis revealed ZFPM1 (friend of GATA protein 1) as top transcription regulator. However, we did not observe any effect of triptolide to the binding of GATA1 in vitro. We confirmed that triptolide inhibited NF-κB activity, and it strongly bound to the pharmacophores of IκB kinase β and NF-κB in silico. Conclusion Triptolide showed promising inhibitory effect toward NF-κB, making it a potential candidate for targeting NF-κB.
Date of acceptance
2021
Autoren
  • Ean-Jeong Seo
  • Mona Dawood
  • Annika K Hult
  • Martin L Olsson
  • Thomas Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/34213719
DOI
10.1007/s10637-021-01137-y
eISSN
1573-0646
Externe Identifier
  • PubMed Central ID: PMC8541937
Ausgabe der Veröffentlichung
6
Zeitschrift
Invest New Drugs
Schlüsselwörter
  • Microarrays
  • Natural products
  • Network pharmacology
  • Phytochemicals
  • Precision medicine
  • Cell Line, Tumor
  • Cell Survival
  • Diterpenes
  • Electrophoretic Mobility Shift Assay
  • Epoxy Compounds
  • GATA1 Transcription Factor
  • Humans
  • Molecular Docking Simulation
  • NF-kappa B
  • Network Pharmacology
  • Phenanthrenes
  • Protein Binding
  • RNA, Messenger
  • Transcription Factors
Sprache
eng
Country
United States
Paginierung
1523 - 1537
PII
10.1007/s10637-021-01137-y
Datum der Veröffentlichung
2021
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2022
Titel
Network pharmacology of triptolide in cancer cells: implications for transcription factor binding.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
39

Data source: PubMed

Author's licence
CC-BY
Autoren
  • Ean-Jeong Seo
  • Mona Dawood
  • Annika K Hult
  • Martin L Olsson
  • Thomas Efferth
Hosting institution
Universitätsbibliothek Mainz
Sammlungen
  • JGU-Publikationen
Resource version
Published version
DOI
10.1007/s10637-021-01137-y
File(s) embargoed
false
Open access
true
ISSN
1573-0646
Zeitschrift
Investigational new drugs
Schlüsselwörter
  • 570 Biowissenschaften
  • 570 Life sciences
  • 610 Medizin
  • 610 Medical sciences
Sprache
eng
Open access status
Open Access
Paginierung
1523 - 1537
Datum der Veröffentlichung
2021
Public URL
https://openscience.ub.uni-mainz.de/handle/20.500.12030/7488
Herausgeber
Springer Science + Business Media B.V.
Datum der Datenerfassung
2022
Datum, an dem der Datensatz öffentlich gemacht wurde
2022
Zugang
Public
Titel
Network pharmacology of triptolide in cancer cells : implications for transcription factor binding
Ausgabe der Zeitschrift
39

Files

network_pharmacology_of_tript-20220729131545075.pdf

Data source: OPENSCIENCE.UB

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