The Novel Artemisinin Dimer Isoniazide ELI-XXIII-98-2 Induces c-MYC Inhibition, DNA Damage, and Autophagy in Leukemia Cells
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Mohamed Elbadawi
- Joelle C Boulos
- Mona Dawood
- Min Zhou
- Waseem Gul
- Mahmoud A ElSohly
- Sabine M Klauck
- Thomas Efferth
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000979368000001&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.3390/pharmaceutics15041107
- eISSN
- 1999-4923
- Externe Identifier
- Clarivate Analytics Document Solution ID: F0MG4
- PubMed Identifier: 37111592
- Ausgabe der Veröffentlichung
- 4
- Zeitschrift
- PHARMACEUTICS
- Schlüsselwörter
- artemisinin
- cell death
- chemotherapy
- leukemia
- oncogenes
- sesquiterpenoids
- Artikelnummer
- ARTN 1107
- Datum der Veröffentlichung
- 2023
- Status
- Published
- Titel
- The Novel Artemisinin Dimer Isoniazide ELI-XXIII-98-2 Induces c-MYC Inhibition, DNA Damage, and Autophagy in Leukemia Cells
- Sub types
- Article
- Ausgabe der Zeitschrift
- 15
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Abstract
- <jats:p>The proto-oncogenic transcription factor c-MYC plays a pivotal role in the development of tumorigenesis, cellular proliferation, and the control of cell death. Its expression is frequently altered in many cancer types, including hematological malignancies such as leukemia. The dimer isoniazide ELI-XXIII-98-2 is a derivative of the natural product artemisinin, with two artemisinin molecules and an isoniazide moiety as a linker in between them. In this study, we aimed to study the anticancer activity and the molecular mechanisms of this dimer molecule in drug-sensitive CCRF-CEM leukemia cells and their corresponding multidrug-resistant CEM/ADR5000 sub-line. The growth inhibitory activity was studied using the resazurin assay. To reveal the molecular mechanisms underlying the growth inhibitory activity, we performed in silico molecular docking, followed by several in vitro approaches such as the MYC reporter assay, microscale thermophoresis, microarray analyses, immunoblotting, qPCR, and comet assay. The artemisinin dimer isoniazide showed a potent growth inhibitory activity in CCRF-CEM but a 12-fold cross-resistance in multidrug-resistant CEM/ADR5000 cells. The molecular docking of artemisinin dimer isoniazide with c-MYC revealed a good binding (lowest binding energy of −9.84 ± 0.3 kcal/mol) and a predicted inhibition constant (pKi) of 66.46 ± 29.5 nM, which was confirmed by microscale thermophoresis and MYC reporter cell assays. Furthermore, c-MYC expression was downregulated by this compound in microarray hybridization and Western blotting analyses. Finally, the artemisinin dimer isoniazide modulated the expression of autophagy markers (LC3B and p62) and the DNA damage marker pH2AX, indicating the stimulation of both autophagy and DNA damage, respectively. Additionally, DNA double-strand breaks were observed in the alkaline comet assay. DNA damage, apoptosis, and autophagy induction could be attributed to the inhibition of c-MYC by ELI-XXIII-98-2.</jats:p>
- Autoren
- Mohamed Elbadawi
- Joelle C Boulos
- Mona Dawood
- Min Zhou
- Waseem Gul
- Mahmoud A ElSohly
- Sabine M Klauck
- Thomas Efferth
- DOI
- 10.3390/pharmaceutics15041107
- eISSN
- 1999-4923
- Ausgabe der Veröffentlichung
- 4
- Zeitschrift
- Pharmaceutics
- Sprache
- en
- Online publication date
- 2023
- Paginierung
- 1107 - 1107
- Status
- Published online
- Herausgeber
- MDPI AG
- Herausgeber URL
- http://dx.doi.org/10.3390/pharmaceutics15041107
- Datum der Datenerfassung
- 2023
- Titel
- The Novel Artemisinin Dimer Isoniazide ELI-XXIII-98-2 Induces c-MYC Inhibition, DNA Damage, and Autophagy in Leukemia Cells
- Ausgabe der Zeitschrift
- 15
Data source: Crossref
- Abstract
- The proto-oncogenic transcription factor c-MYC plays a pivotal role in the development of tumorigenesis, cellular proliferation, and the control of cell death. Its expression is frequently altered in many cancer types, including hematological malignancies such as leukemia. The dimer isoniazide ELI-XXIII-98-2 is a derivative of the natural product artemisinin, with two artemisinin molecules and an isoniazide moiety as a linker in between them. In this study, we aimed to study the anticancer activity and the molecular mechanisms of this dimer molecule in drug-sensitive CCRF-CEM leukemia cells and their corresponding multidrug-resistant CEM/ADR5000 sub-line. The growth inhibitory activity was studied using the resazurin assay. To reveal the molecular mechanisms underlying the growth inhibitory activity, we performed in silico molecular docking, followed by several in vitro approaches such as the MYC reporter assay, microscale thermophoresis, microarray analyses, immunoblotting, qPCR, and comet assay. The artemisinin dimer isoniazide showed a potent growth inhibitory activity in CCRF-CEM but a 12-fold cross-resistance in multidrug-resistant CEM/ADR5000 cells. The molecular docking of artemisinin dimer isoniazide with c-MYC revealed a good binding (lowest binding energy of -9.84 ± 0.3 kcal/mol) and a predicted inhibition constant (pKi) of 66.46 ± 29.5 nM, which was confirmed by microscale thermophoresis and MYC reporter cell assays. Furthermore, c-MYC expression was downregulated by this compound in microarray hybridization and Western blotting analyses. Finally, the artemisinin dimer isoniazide modulated the expression of autophagy markers (LC3B and p62) and the DNA damage marker pH2AX, indicating the stimulation of both autophagy and DNA damage, respectively. Additionally, DNA double-strand breaks were observed in the alkaline comet assay. DNA damage, apoptosis, and autophagy induction could be attributed to the inhibition of c-MYC by ELI-XXIII-98-2.
- Addresses
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University-Mainz, 55128 Mainz, Germany.
- Autoren
- Mohamed Elbadawi
- Joelle C Boulos
- Mona Dawood
- Min Zhou
- Waseem Gul
- Mahmoud A ElSohly
- Sabine M Klauck
- Thomas Efferth
- DOI
- 10.3390/pharmaceutics15041107
- eISSN
- 1999-4923
- Externe Identifier
- PubMed Identifier: 37111592
- PubMed Central ID: PMC10144546
- Funding acknowledgements
- Theophrastus Paracelsus Foundation:
- Open access
- true
- ISSN
- 1999-4923
- Ausgabe der Veröffentlichung
- 4
- Zeitschrift
- Pharmaceutics
- Sprache
- eng
- Medium
- Electronic
- Online publication date
- 2023
- Open access status
- Open Access
- Paginierung
- 1107
- Datum der Veröffentlichung
- 2023
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2023
- Titel
- The Novel Artemisinin Dimer Isoniazide ELI-XXIII-98-2 Induces c-MYC Inhibition, DNA Damage, and Autophagy in Leukemia Cells.
- Sub types
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 15
Files
https://www.mdpi.com/1999-4923/15/4/1107/pdf?version=1680226815 https://europepmc.org/articles/PMC10144546?pdf=render
Data source: Europe PubMed Central
- Abstract
- The proto-oncogenic transcription factor c-MYC plays a pivotal role in the development of tumorigenesis, cellular proliferation, and the control of cell death. Its expression is frequently altered in many cancer types, including hematological malignancies such as leukemia. The dimer isoniazide ELI-XXIII-98-2 is a derivative of the natural product artemisinin, with two artemisinin molecules and an isoniazide moiety as a linker in between them. In this study, we aimed to study the anticancer activity and the molecular mechanisms of this dimer molecule in drug-sensitive CCRF-CEM leukemia cells and their corresponding multidrug-resistant CEM/ADR5000 sub-line. The growth inhibitory activity was studied using the resazurin assay. To reveal the molecular mechanisms underlying the growth inhibitory activity, we performed in silico molecular docking, followed by several in vitro approaches such as the MYC reporter assay, microscale thermophoresis, microarray analyses, immunoblotting, qPCR, and comet assay. The artemisinin dimer isoniazide showed a potent growth inhibitory activity in CCRF-CEM but a 12-fold cross-resistance in multidrug-resistant CEM/ADR5000 cells. The molecular docking of artemisinin dimer isoniazide with c-MYC revealed a good binding (lowest binding energy of -9.84 ± 0.3 kcal/mol) and a predicted inhibition constant (pKi) of 66.46 ± 29.5 nM, which was confirmed by microscale thermophoresis and MYC reporter cell assays. Furthermore, c-MYC expression was downregulated by this compound in microarray hybridization and Western blotting analyses. Finally, the artemisinin dimer isoniazide modulated the expression of autophagy markers (LC3B and p62) and the DNA damage marker pH2AX, indicating the stimulation of both autophagy and DNA damage, respectively. Additionally, DNA double-strand breaks were observed in the alkaline comet assay. DNA damage, apoptosis, and autophagy induction could be attributed to the inhibition of c-MYC by ELI-XXIII-98-2.
- Date of acceptance
- 2023
- Autoren
- Mohamed Elbadawi
- Joelle C Boulos
- Mona Dawood
- Min Zhou
- Waseem Gul
- Mahmoud A ElSohly
- Sabine M Klauck
- Thomas Efferth
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/37111592
- DOI
- 10.3390/pharmaceutics15041107
- Externe Identifier
- PubMed Central ID: PMC10144546
- ISSN
- 1999-4923
- Ausgabe der Veröffentlichung
- 4
- Zeitschrift
- Pharmaceutics
- Schlüsselwörter
- artemisinin
- cell death
- chemotherapy
- leukemia
- oncogenes
- sesquiterpenoids
- Sprache
- eng
- Country
- Switzerland
- PII
- pharmaceutics15041107
- Datum der Veröffentlichung
- 2023
- Status
- Published online
- Titel
- The Novel Artemisinin Dimer Isoniazide ELI-XXIII-98-2 Induces c-MYC Inhibition, DNA Damage, and Autophagy in Leukemia Cells.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 15
Data source: PubMed
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