Oridonin Targets Multiple Drug-Resistant Tumor Cells as Determined by in Silico and in Vitro Analyses
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Onat Kadioglu
- Mohamed Saeed
- Victor Kuete
- Henry J Greten
- Thomas Efferth
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000430098000001&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.3389/fphar.2018.00355
- Externe Identifier
- Clarivate Analytics Document Solution ID: GC9DP
- PubMed Identifier: 29713280
- ISSN
- 1663-9812
- Zeitschrift
- FRONTIERS IN PHARMACOLOGY
- Schlüsselwörter
- cluster analysis
- drug resistance
- microarray
- molecular docking
- molecular dynamics
- natural compound
- Artikelnummer
- ARTN 355
- Datum der Veröffentlichung
- 2018
- Status
- Published
- Titel
- Oridonin Targets Multiple Drug-Resistant Tumor Cells as Determined by <i>in Silico</i> and <i>in Vitro</i> Analyses
- Sub types
- Article
- Ausgabe der Zeitschrift
- 9
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Autoren
- Onat Kadioglu
- Mohamed Saeed
- Victor Kuete
- Henry J Greten
- Thomas Efferth
- DOI
- 10.3389/fphar.2018.00355
- eISSN
- 1663-9812
- Zeitschrift
- Frontiers in Pharmacology
- Online publication date
- 2018
- Status
- Published online
- Herausgeber
- Frontiers Media SA
- Herausgeber URL
- http://dx.doi.org/10.3389/fphar.2018.00355
- Datum der Datenerfassung
- 2022
- Titel
- Oridonin Targets Multiple Drug-Resistant Tumor Cells as Determined by in Silico and in Vitro Analyses
- Ausgabe der Zeitschrift
- 9
Data source: Crossref
- Abstract
- Drug resistance is one of the main reasons of chemotherapy failure. Therefore, overcoming drug resistance is an invaluable approach to identify novel anticancer drugs that have the potential to bypass or overcome resistance to established drugs and to substantially increase life span of cancer patients for effective chemotherapy. Oridonin is a cytotoxic diterpenoid isolated from <i>Rabdosia rubescens</i> with <i>in vivo</i> anticancer activity. In the present study, we evaluated the cytotoxicity of oridonin toward a panel of drug-resistant cancer cells overexpressing ABCB1, ABCG2, or ΔEGFR or with a knockout deletion of TP53. Interestingly, oridonin revealed lower degree of resistance than the control drug, doxorubicin. Molecular docking analyses pointed out that oridonin can interact with Akt/EGFR pathway proteins with comparable binding energies and similar docking poses as the known inhibitors. Molecular dynamics results validated the stable conformation of oridonin docking pose on Akt kinase domain. Western blot experiments clearly revealed dose-dependent downregulation of Akt and STAT3. Pharmacogenomics analyses pointed to a mRNA signature that predicted sensitivity and resistance to oridonin. In conclusion, oridonin bypasses major drug resistance mechanisms and targets Akt pathway and might be effective toward drug refractory tumors. The identification of oridonin-specific gene expressions may be useful for the development of personalized treatment approaches.
- Addresses
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University Mainz, Mainz, Germany.
- Autoren
- Onat Kadioglu
- Mohamed Saeed
- Victor Kuete
- Henry J Greten
- Thomas Efferth
- Thomas Efferth
- DOI
- 10.3389/fphar.2018.00355
- eISSN
- 1663-9812
- Externe Identifier
- PubMed Identifier: 29713280
- PubMed Central ID: PMC5911471
- Open access
- true
- ISSN
- 1663-9812
- Zeitschrift
- Frontiers in pharmacology
- Sprache
- eng
- Medium
- Electronic-eCollection
- Online publication date
- 2018
- Open access status
- Open Access
- Paginierung
- 355
- Datum der Veröffentlichung
- 2018
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2018
- Titel
- Oridonin Targets Multiple Drug-Resistant Tumor Cells as Determined by <i>in Silico</i> and <i>in Vitro</i> Analyses.
- Sub types
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 9
Files
https://www.frontiersin.org/articles/10.3389/fphar.2018.00355/pdf https://europepmc.org/articles/PMC5911471?pdf=render
Data source: Europe PubMed Central
- Abstract
- Drug resistance is one of the main reasons of chemotherapy failure. Therefore, overcoming drug resistance is an invaluable approach to identify novel anticancer drugs that have the potential to bypass or overcome resistance to established drugs and to substantially increase life span of cancer patients for effective chemotherapy. Oridonin is a cytotoxic diterpenoid isolated from Rabdosia rubescens with in vivo anticancer activity. In the present study, we evaluated the cytotoxicity of oridonin toward a panel of drug-resistant cancer cells overexpressing ABCB1, ABCG2, or ΔEGFR or with a knockout deletion of TP53. Interestingly, oridonin revealed lower degree of resistance than the control drug, doxorubicin. Molecular docking analyses pointed out that oridonin can interact with Akt/EGFR pathway proteins with comparable binding energies and similar docking poses as the known inhibitors. Molecular dynamics results validated the stable conformation of oridonin docking pose on Akt kinase domain. Western blot experiments clearly revealed dose-dependent downregulation of Akt and STAT3. Pharmacogenomics analyses pointed to a mRNA signature that predicted sensitivity and resistance to oridonin. In conclusion, oridonin bypasses major drug resistance mechanisms and targets Akt pathway and might be effective toward drug refractory tumors. The identification of oridonin-specific gene expressions may be useful for the development of personalized treatment approaches.
- Date of acceptance
- 2018
- Autoren
- Onat Kadioglu
- Mohamed Saeed
- Victor Kuete
- Henry J Greten
- Thomas Efferth
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/29713280
- DOI
- 10.3389/fphar.2018.00355
- Externe Identifier
- PubMed Central ID: PMC5911471
- ISSN
- 1663-9812
- Zeitschrift
- Front Pharmacol
- Schlüsselwörter
- cluster analysis
- drug resistance
- microarray
- molecular docking
- molecular dynamics
- natural compound
- Sprache
- eng
- Country
- Switzerland
- Paginierung
- 355
- Datum der Veröffentlichung
- 2018
- Status
- Published online
- Titel
- Oridonin Targets Multiple Drug-Resistant Tumor Cells as Determined by in Silico and in Vitro Analyses.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 9
Data source: PubMed
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