Multifactorial Modes of Action of Arsenic Trioxide in Cancer Cells as Analyzed by Classical and Network Pharmacology
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Mona Dawood
- Sami Hamdoun
- Thomas Efferth
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000426187900001&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.3389/fphar.2018.00143
- eISSN
- 1663-9812
- Externe Identifier
- Clarivate Analytics Document Solution ID: FX6IR
- PubMed Identifier: 29535630
- Zeitschrift
- FRONTIERS IN PHARMACOLOGY
- Schlüsselwörter
- trioxide
- drug resistance
- pharmacogenomics
- AP-1
- NF-kappa B
- Artikelnummer
- ARTN 143
- Datum der Veröffentlichung
- 2018
- Status
- Published
- Titel
- Multifactorial Modes of Action of Arsenic Trioxide in Cancer Cells as Analyzed by Classical and Network Pharmacology
- Sub types
- Article
- Ausgabe der Zeitschrift
- 9
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Autoren
- Mona Dawood
- Sami Hamdoun
- Thomas Efferth
- DOI
- 10.3389/fphar.2018.00143
- 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.2018.00143
- Datum der Datenerfassung
- 2020
- Titel
- Multifactorial Modes of Action of Arsenic Trioxide in Cancer Cells as Analyzed by Classical and Network Pharmacology
- Ausgabe der Zeitschrift
- 9
Data source: Crossref
- Abstract
- Arsenic trioxide is a traditional remedy in Chinese Medicine since ages. Nowadays, it is clinically used to treat acute promyelocytic leukemia (APL) by targeting PML/RARA. However, the drug's activity is broader and the mechanisms of action in other tumor types remain unclear. In this study, we investigated molecular modes of action by classical and network pharmacological approaches. CEM/ADR5000 resistance leukemic cells were similar sensitive to As<sub>2</sub>O<sub>3</sub> as their wild-type counterpart CCRF-CEM (resistance ratio: 1.88). Drug-resistant U87.MG ΔEGFR glioblastoma cells harboring mutated epidermal growth factor receptor were even more sensitive (collateral sensitive) than wild-type U87.MG cells (resistance ratio: 0.33). HCT-116 colon carcinoma p53<sup>-/-</sup> knockout cells were 7.16-fold resistant toward As<sub>2</sub>O<sub>3</sub> compared to wild-type cells. Forty genes determining cellular responsiveness to As<sub>2</sub>O<sub>3</sub> were identified by microarray and COMPARE analyses in 58 cell lines of the NCI panel. Hierarchical cluster analysis-based heat mapping revealed significant differences between As<sub>2</sub>O<sub>3</sub> sensitive cell lines and resistant cell lines with <i>p</i>-value: 1.86 × 10<sup>-5</sup>. The genes were subjected to Galaxy Cistrome gene promoter transcription factor analysis to predict the binding of transcription factors. We have exemplarily chosen NF-kB and AP-1, and indeed As<sub>2</sub>O<sub>3</sub> dose-dependently inhibited the promoter activity of these two transcription factors in reporter cell lines. Furthermore, the genes identified here and those published in the literature were assembled and subjected to Ingenuity Pathway Analysis for comprehensive network pharmacological approaches that included all known factors of resistance of tumor cells to As<sub>2</sub>O<sub>3</sub>. In addition to pathways related to the anticancer effects of As<sub>2</sub>O<sub>3</sub>, several neurological pathways were identified. As arsenic is well-known to exert neurotoxicity, these pathways might account for neurological side effects. In conclusion, the activity of As<sub>2</sub>O<sub>3</sub> is not restricted to acute promyelocytic leukemia. In addition to PML/RARA, numerous other genes belonging to diverse functional classes may also contribute to its cytotoxicity. Network pharmacology is suited to unravel the multifactorial modes of action of As<sub>2</sub>O<sub>3</sub>.
- Addresses
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
- Autoren
- Mona Dawood
- Sami Hamdoun
- Thomas Efferth
- Thomas Efferth
- DOI
- 10.3389/fphar.2018.00143
- eISSN
- 1663-9812
- Externe Identifier
- PubMed Identifier: 29535630
- PubMed Central ID: PMC5835320
- 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
- 143
- Datum der Veröffentlichung
- 2018
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2018
- Titel
- Multifactorial Modes of Action of Arsenic Trioxide in Cancer Cells as Analyzed by Classical and Network Pharmacology.
- Sub types
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 9
Files
https://www.frontiersin.org/articles/10.3389/fphar.2018.00143/pdf https://europepmc.org/articles/PMC5835320?pdf=render
Data source: Europe PubMed Central
- Abstract
- Arsenic trioxide is a traditional remedy in Chinese Medicine since ages. Nowadays, it is clinically used to treat acute promyelocytic leukemia (APL) by targeting PML/RARA. However, the drug's activity is broader and the mechanisms of action in other tumor types remain unclear. In this study, we investigated molecular modes of action by classical and network pharmacological approaches. CEM/ADR5000 resistance leukemic cells were similar sensitive to As2O3 as their wild-type counterpart CCRF-CEM (resistance ratio: 1.88). Drug-resistant U87.MG ΔEGFR glioblastoma cells harboring mutated epidermal growth factor receptor were even more sensitive (collateral sensitive) than wild-type U87.MG cells (resistance ratio: 0.33). HCT-116 colon carcinoma p53-/- knockout cells were 7.16-fold resistant toward As2O3 compared to wild-type cells. Forty genes determining cellular responsiveness to As2O3 were identified by microarray and COMPARE analyses in 58 cell lines of the NCI panel. Hierarchical cluster analysis-based heat mapping revealed significant differences between As2O3 sensitive cell lines and resistant cell lines with p-value: 1.86 × 10-5. The genes were subjected to Galaxy Cistrome gene promoter transcription factor analysis to predict the binding of transcription factors. We have exemplarily chosen NF-kB and AP-1, and indeed As2O3 dose-dependently inhibited the promoter activity of these two transcription factors in reporter cell lines. Furthermore, the genes identified here and those published in the literature were assembled and subjected to Ingenuity Pathway Analysis for comprehensive network pharmacological approaches that included all known factors of resistance of tumor cells to As2O3. In addition to pathways related to the anticancer effects of As2O3, several neurological pathways were identified. As arsenic is well-known to exert neurotoxicity, these pathways might account for neurological side effects. In conclusion, the activity of As2O3 is not restricted to acute promyelocytic leukemia. In addition to PML/RARA, numerous other genes belonging to diverse functional classes may also contribute to its cytotoxicity. Network pharmacology is suited to unravel the multifactorial modes of action of As2O3.
- Date of acceptance
- 2018
- Autoren
- Mona Dawood
- Sami Hamdoun
- Thomas Efferth
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/29535630
- DOI
- 10.3389/fphar.2018.00143
- Externe Identifier
- PubMed Central ID: PMC5835320
- ISSN
- 1663-9812
- Zeitschrift
- Front Pharmacol
- Schlüsselwörter
- AP-1
- NF-κB
- arsenic trioxide
- drug resistance
- pharmacogenomics
- Sprache
- eng
- Country
- Switzerland
- Paginierung
- 143
- Datum der Veröffentlichung
- 2018
- Status
- Published online
- Titel
- Multifactorial Modes of Action of Arsenic Trioxide in Cancer Cells as Analyzed by Classical and Network Pharmacology.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 9
Data source: PubMed
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