Modes of Action of a Novel c-MYC Inhibiting 1,2,4-Oxadiazole Derivative in Leukemia and Breast Cancer Cells
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Min Zhou
- Joelle C Boulos
- Ejlal A Omer
- Sabine M Klauck
- Thomas Efferth
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:001046238000001&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.3390/molecules28155658
- eISSN
- 1420-3049
- Externe Identifier
- Clarivate Analytics Document Solution ID: O8KH4
- PubMed Identifier: 37570631
- Ausgabe der Veröffentlichung
- 15
- Zeitschrift
- MOLECULES
- Schlüsselwörter
- 1
- 2
- 4-oxadiazole
- c-MYC inhibitor
- leukemia
- natural product derivative
- oncogenes
- triple-negative breast cancer
- Artikelnummer
- ARTN 5658
- Datum der Veröffentlichung
- 2023
- Status
- Published
- Titel
- Modes of Action of a Novel c-MYC Inhibiting 1,2,4-Oxadiazole Derivative in Leukemia and Breast Cancer Cells
- Sub types
- Article
- Ausgabe der Zeitschrift
- 28
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Abstract
- <jats:p>The c-MYC oncogene regulates multiple cellular activities and is a potent driver of many highly aggressive human cancers, such as leukemia and triple-negative breast cancer. The oxadiazole class of compounds has gained increasing interest for its anticancer activities. The aim of this study was to investigate the molecular modes of action of a 1,2,4-oxadiazole derivative (ZINC15675948) as a c-MYC inhibitor. ZINC15675948 displayed profound cytotoxicity at the nanomolar range in CCRF-CEM leukemia and MDA-MB-231-pcDNA3 breast cancer cells. Multidrug-resistant sublines thereof (i.e., CEM/ADR5000 and MDA-MB-231-BCRP) were moderately cross-resistant to this compound (<10-fold). Molecular docking and microscale thermophoresis revealed a strong binding of ZINC15675948 to c-MYC by interacting close to the c-MYC/MAX interface. A c-MYC reporter assay demonstrated that ZINC15675948 inhibited c-MYC activity. Western blotting and qRT-PCR showed that c-MYC expression was downregulated by ZINC15675948. Applying microarray hybridization and signaling pathway analyses, ZINC15675948 affected signaling routes downstream of c-MYC in both leukemia and breast cancer cells as demonstrated by the induction of DNA damage using single cell gel electrophoresis (alkaline comet assay) and induction of apoptosis using flow cytometry. ZINC15675948 also caused G2/M phase and S phase arrest in CCRF-CEM cells and MDA-MB-231-pcDNA3 cells, respectively, accompanied by the downregulation of CDK1 and p-CDK2 expression using western blotting. Autophagy induction was observed in CCRF-CEM cells but not MDA-MB-231-pcDNA3 cells. Furthermore, microarray-based mRNA expression profiling indicated that ZINC15675948 may target c-MYC-regulated ubiquitination, since the novel ubiquitin ligase (ELL2) was upregulated in the absence of c-MYC expression. We propose that ZINC15675948 is a promising natural product-derived compound targeting c-MYC in c-MYC-driven cancers through DNA damage, cell cycle arrest, and apoptosis.</jats:p>
- Autoren
- Min Zhou
- Joelle C Boulos
- Ejlal A Omer
- Sabine M Klauck
- Thomas Efferth
- DOI
- 10.3390/molecules28155658
- eISSN
- 1420-3049
- Ausgabe der Veröffentlichung
- 15
- Zeitschrift
- Molecules
- Sprache
- en
- Online publication date
- 2023
- Paginierung
- 5658 - 5658
- Status
- Published online
- Herausgeber
- MDPI AG
- Herausgeber URL
- http://dx.doi.org/10.3390/molecules28155658
- Datum der Datenerfassung
- 2023
- Titel
- Modes of Action of a Novel c-MYC Inhibiting 1,2,4-Oxadiazole Derivative in Leukemia and Breast Cancer Cells
- Ausgabe der Zeitschrift
- 28
Data source: Crossref
- Abstract
- The <i>c-MYC</i> oncogene regulates multiple cellular activities and is a potent driver of many highly aggressive human cancers, such as leukemia and triple-negative breast cancer. The oxadiazole class of compounds has gained increasing interest for its anticancer activities. The aim of this study was to investigate the molecular modes of action of a 1,2,4-oxadiazole derivative (ZINC15675948) as a c-MYC inhibitor. ZINC15675948 displayed profound cytotoxicity at the nanomolar range in CCRF-CEM leukemia and MDA-MB-231-pcDNA3 breast cancer cells. Multidrug-resistant sublines thereof (i.e., CEM/ADR5000 and MDA-MB-231-BCRP) were moderately cross-resistant to this compound (<10-fold). Molecular docking and microscale thermophoresis revealed a strong binding of ZINC15675948 to c-MYC by interacting close to the c-MYC/MAX interface. A c-MYC reporter assay demonstrated that ZINC15675948 inhibited c-MYC activity. Western blotting and qRT-PCR showed that c-MYC expression was downregulated by ZINC15675948. Applying microarray hybridization and signaling pathway analyses, ZINC15675948 affected signaling routes downstream of c-MYC in both leukemia and breast cancer cells as demonstrated by the induction of DNA damage using single cell gel electrophoresis (alkaline comet assay) and induction of apoptosis using flow cytometry. ZINC15675948 also caused G2/M phase and S phase arrest in CCRF-CEM cells and MDA-MB-231-pcDNA3 cells, respectively, accompanied by the downregulation of CDK1 and p-CDK2 expression using western blotting. Autophagy induction was observed in CCRF-CEM cells but not MDA-MB-231-pcDNA3 cells. Furthermore, microarray-based mRNA expression profiling indicated that ZINC15675948 may target c-MYC-regulated ubiquitination, since the novel ubiquitin ligase (ELL2) was upregulated in the absence of c-MYC expression. We propose that ZINC15675948 is a promising natural product-derived compound targeting c-MYC in c-MYC-driven cancers through DNA damage, cell cycle arrest, and apoptosis.
- Addresses
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University-Mainz, Staudinger Weg 5, 55128 Mainz, Germany.
- Autoren
- Min Zhou
- Joelle C Boulos
- Ejlal A Omer
- Sabine M Klauck
- Thomas Efferth
- DOI
- 10.3390/molecules28155658
- eISSN
- 1420-3049
- Externe Identifier
- PubMed Identifier: 37570631
- PubMed Central ID: PMC10419799
- Open access
- true
- ISSN
- 1420-3049
- Ausgabe der Veröffentlichung
- 15
- Zeitschrift
- Molecules (Basel, Switzerland)
- Schlüsselwörter
- Cell Line, Tumor
- Humans
- Leukemia
- Breast Neoplasms
- Neoplasm Proteins
- Transcriptional Elongation Factors
- Plant Extracts
- Antineoplastic Agents, Phytogenic
- Apoptosis
- Drug Resistance, Neoplasm
- Female
- Molecular Docking Simulation
- ATP Binding Cassette Transporter, Subfamily G, Member 2
- Sprache
- eng
- Medium
- Electronic
- Online publication date
- 2023
- Open access status
- Open Access
- Paginierung
- 5658
- Datum der Veröffentlichung
- 2023
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2023
- Titel
- Modes of Action of a Novel c-MYC Inhibiting 1,2,4-Oxadiazole Derivative in Leukemia and Breast Cancer Cells.
- Sub types
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 28
Files
https://europepmc.org/articles/PMC10419799?pdf=render
Data source: Europe PubMed Central
- Abstract
- The c-MYC oncogene regulates multiple cellular activities and is a potent driver of many highly aggressive human cancers, such as leukemia and triple-negative breast cancer. The oxadiazole class of compounds has gained increasing interest for its anticancer activities. The aim of this study was to investigate the molecular modes of action of a 1,2,4-oxadiazole derivative (ZINC15675948) as a c-MYC inhibitor. ZINC15675948 displayed profound cytotoxicity at the nanomolar range in CCRF-CEM leukemia and MDA-MB-231-pcDNA3 breast cancer cells. Multidrug-resistant sublines thereof (i.e., CEM/ADR5000 and MDA-MB-231-BCRP) were moderately cross-resistant to this compound (<10-fold). Molecular docking and microscale thermophoresis revealed a strong binding of ZINC15675948 to c-MYC by interacting close to the c-MYC/MAX interface. A c-MYC reporter assay demonstrated that ZINC15675948 inhibited c-MYC activity. Western blotting and qRT-PCR showed that c-MYC expression was downregulated by ZINC15675948. Applying microarray hybridization and signaling pathway analyses, ZINC15675948 affected signaling routes downstream of c-MYC in both leukemia and breast cancer cells as demonstrated by the induction of DNA damage using single cell gel electrophoresis (alkaline comet assay) and induction of apoptosis using flow cytometry. ZINC15675948 also caused G2/M phase and S phase arrest in CCRF-CEM cells and MDA-MB-231-pcDNA3 cells, respectively, accompanied by the downregulation of CDK1 and p-CDK2 expression using western blotting. Autophagy induction was observed in CCRF-CEM cells but not MDA-MB-231-pcDNA3 cells. Furthermore, microarray-based mRNA expression profiling indicated that ZINC15675948 may target c-MYC-regulated ubiquitination, since the novel ubiquitin ligase (ELL2) was upregulated in the absence of c-MYC expression. We propose that ZINC15675948 is a promising natural product-derived compound targeting c-MYC in c-MYC-driven cancers through DNA damage, cell cycle arrest, and apoptosis.
- Date of acceptance
- 2023
- Autoren
- Min Zhou
- Joelle C Boulos
- Ejlal A Omer
- Sabine M Klauck
- Thomas Efferth
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/37570631
- DOI
- 10.3390/molecules28155658
- eISSN
- 1420-3049
- Externe Identifier
- PubMed Central ID: PMC10419799
- Ausgabe der Veröffentlichung
- 15
- Zeitschrift
- Molecules
- Schlüsselwörter
- 1,2,4-oxadiazole
- c-MYC inhibitor
- leukemia
- natural product derivative
- oncogenes
- triple-negative breast cancer
- Humans
- Female
- Plant Extracts
- Cell Line, Tumor
- Breast Neoplasms
- Molecular Docking Simulation
- ATP Binding Cassette Transporter, Subfamily G, Member 2
- Antineoplastic Agents, Phytogenic
- Drug Resistance, Neoplasm
- Neoplasm Proteins
- Apoptosis
- Leukemia
- Transcriptional Elongation Factors
- Sprache
- eng
- Country
- Switzerland
- PII
- molecules28155658
- Datum der Veröffentlichung
- 2023
- Status
- Published online
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2023
- Titel
- Modes of Action of a Novel c-MYC Inhibiting 1,2,4-Oxadiazole Derivative in Leukemia and Breast Cancer Cells.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 28
Data source: PubMed
- Beziehungen:
-