The cardiac glycoside ZINC253504760 induces parthanatos-type cell death and G2/M arrest via downregulation of MEK1/2 phosphorylation in leukemia cells

Publication type:
Journal article
Metadata:
Autoren
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:001011266200002&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1007/s10565-023-09813-w
eISSN
1573-6822
Externe Identifier
  • Clarivate Analytics Document Solution ID: CI0K2
  • PubMed Identifier: 37322258
ISSN
0742-2091
Ausgabe der Veröffentlichung
6
Zeitschrift
CELL BIOLOGY AND TOXICOLOGY
Schlüsselwörter
  • Cardiac glycosides
  • Leukemia
  • MEK inhibitors
  • Parthanatos
  • Synthetic derivative
  • Transcriptomics
Paginierung
2971 - 2997
Datum der Veröffentlichung
2023
Status
Published
Titel
The cardiac glycoside ZINC253504760 induces parthanatos-type cell death and G2/M arrest via downregulation of MEK1/2 phosphorylation in leukemia cells
Sub types
  • Article
Ausgabe der Zeitschrift
39

Data source: Web of Science (Lite)

Other metadata sources:
Abstract
<jats:title>Abstract</jats:title><jats:p>Overcoming multidrug resistance (MDR) represents a major obstacle in cancer chemotherapy. Cardiac glycosides (CGs) are efficient in the treatment of heart failure and recently emerged in a new role in the treatment of cancer. ZINC253504760, a synthetic cardenolide that is structurally similar to well-known GCs, digitoxin and digoxin, has not been investigated yet. This study aims to investigate the cytotoxicity of ZINC253504760 on MDR cell lines and its molecular mode of action for cancer treatment. Four drug-resistant cell lines (P-glycoprotein-, ABCB5-, and EGFR-overexpressing cells, and TP53-knockout cells) did not show cross-resistance to ZINC253504760 except BCRP-overexpressing cells. Transcriptomic profiling indicated that cell death and survival as well as cell cycle (G2/M damage) were the top cellular functions affected by ZINC253504760 in CCRF-CEM cells, while CDK1 was linked with the downregulation of MEK and ERK. With flow cytometry, ZINC253504760 induced G2/M phase arrest. Interestingly, ZINC253504760 induced a novel state-of-the-art mode of cell death (parthanatos) through PARP and PAR overexpression as shown by western blotting, apoptosis-inducing factor (AIF) translocation by immunofluorescence, DNA damage by comet assay, and mitochondrial membrane potential collapse by flow cytometry. These results were ROS-independent. Furthermore, ZINC253504760 is an ATP-competitive MEK inhibitor evidenced by its interaction with the MEK phosphorylation site as shown by molecular docking <jats:italic>in silico</jats:italic> and binding to recombinant MEK by microscale thermophoresis <jats:italic>in vitro</jats:italic>. To the best of our knowledge, this is the first time to describe a cardenolide that induces parthanatos in leukemia cells, which may help to improve efforts to overcome drug resistance in cancer.</jats:p> <jats:p><jats:bold>Graphical Abstract</jats:bold></jats:p> <jats:p>A cardiac glycoside compound ZINC253504760 displayed cytotoxicity against different multidrug-resistant cell lines. ZINC253504760 exhibited cytotoxicity in CCRF-CEM leukemia cells by predominantly inducing a new mode of cell death (parthanatos). ZINC253504760 downregulated MEK1/2 phosphorylation and further affected ERK activation, which induced G2/M phase arrest. </jats:p>
Autoren
DOI
10.1007/s10565-023-09813-w
eISSN
1573-6822
ISSN
0742-2091
Ausgabe der Veröffentlichung
6
Zeitschrift
Cell Biology and Toxicology
Sprache
en
Online publication date
2023
Paginierung
2971 - 2997
Datum der Veröffentlichung
2023
Status
Published
Herausgeber
Springer Science and Business Media LLC
Herausgeber URL
http://dx.doi.org/10.1007/s10565-023-09813-w
Datum der Datenerfassung
2023
Titel
The cardiac glycoside ZINC253504760 induces parthanatos-type cell death and G2/M arrest via downregulation of MEK1/2 phosphorylation in leukemia cells
Ausgabe der Zeitschrift
39

Data source: Crossref

Abstract
Overcoming multidrug resistance (MDR) represents a major obstacle in cancer chemotherapy. Cardiac glycosides (CGs) are efficient in the treatment of heart failure and recently emerged in a new role in the treatment of cancer. ZINC253504760, a synthetic cardenolide that is structurally similar to well-known GCs, digitoxin and digoxin, has not been investigated yet. This study aims to investigate the cytotoxicity of ZINC253504760 on MDR cell lines and its molecular mode of action for cancer treatment. Four drug-resistant cell lines (P-glycoprotein-, ABCB5-, and EGFR-overexpressing cells, and TP53-knockout cells) did not show cross-resistance to ZINC253504760 except BCRP-overexpressing cells. Transcriptomic profiling indicated that cell death and survival as well as cell cycle (G2/M damage) were the top cellular functions affected by ZINC253504760 in CCRF-CEM cells, while CDK1 was linked with the downregulation of MEK and ERK. With flow cytometry, ZINC253504760 induced G2/M phase arrest. Interestingly, ZINC253504760 induced a novel state-of-the-art mode of cell death (parthanatos) through PARP and PAR overexpression as shown by western blotting, apoptosis-inducing factor (AIF) translocation by immunofluorescence, DNA damage by comet assay, and mitochondrial membrane potential collapse by flow cytometry. These results were ROS-independent. Furthermore, ZINC253504760 is an ATP-competitive MEK inhibitor evidenced by its interaction with the MEK phosphorylation site as shown by molecular docking in silico and binding to recombinant MEK by microscale thermophoresis in vitro. To the best of our knowledge, this is the first time to describe a cardenolide that induces parthanatos in leukemia cells, which may help to improve efforts to overcome drug resistance in cancer. A cardiac glycoside compound ZINC253504760 displayed cytotoxicity against different multidrug-resistant cell lines. ZINC253504760 exhibited cytotoxicity in CCRF-CEM leukemia cells by predominantly inducing a new mode of cell death (parthanatos). ZINC253504760 downregulated MEK1/2 phosphorylation and further affected ERK activation, which induced G2/M phase arrest.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University-Mainz, Staudinger Weg 5, 55128, Mainz, Germany.
Autoren
DOI
10.1007/s10565-023-09813-w
eISSN
1573-6822
Externe Identifier
  • PubMed Identifier: 37322258
  • PubMed Central ID: PMC10693532
Funding acknowledgements
  • Johannes Gutenberg-Universität Mainz:
Open access
true
ISSN
0742-2091
Ausgabe der Veröffentlichung
6
Zeitschrift
Cell biology and toxicology
Schlüsselwörter
  • Cell Line, Tumor
  • Humans
  • Leukemia
  • Cardenolides
  • Cardiac Glycosides
  • Mitogen-Activated Protein Kinase Kinases
  • Neoplasm Proteins
  • Apoptosis
  • Down-Regulation
  • Phosphorylation
  • Drug Resistance, Neoplasm
  • G2 Phase Cell Cycle Checkpoints
  • Molecular Docking Simulation
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Parthanatos
Sprache
eng
Medium
Print-Electronic
Online publication date
2023
Open access status
Open Access
Paginierung
2971 - 2997
Datum der Veröffentlichung
2023
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
2023
Titel
The cardiac glycoside ZINC253504760 induces parthanatos-type cell death and G2/M arrest via downregulation of MEK1/2 phosphorylation in leukemia cells.
Sub types
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
39

Files

https://europepmc.org/articles/PMC10693532?pdf=render

Data source: Europe PubMed Central

Abstract
Overcoming multidrug resistance (MDR) represents a major obstacle in cancer chemotherapy. Cardiac glycosides (CGs) are efficient in the treatment of heart failure and recently emerged in a new role in the treatment of cancer. ZINC253504760, a synthetic cardenolide that is structurally similar to well-known GCs, digitoxin and digoxin, has not been investigated yet. This study aims to investigate the cytotoxicity of ZINC253504760 on MDR cell lines and its molecular mode of action for cancer treatment. Four drug-resistant cell lines (P-glycoprotein-, ABCB5-, and EGFR-overexpressing cells, and TP53-knockout cells) did not show cross-resistance to ZINC253504760 except BCRP-overexpressing cells. Transcriptomic profiling indicated that cell death and survival as well as cell cycle (G2/M damage) were the top cellular functions affected by ZINC253504760 in CCRF-CEM cells, while CDK1 was linked with the downregulation of MEK and ERK. With flow cytometry, ZINC253504760 induced G2/M phase arrest. Interestingly, ZINC253504760 induced a novel state-of-the-art mode of cell death (parthanatos) through PARP and PAR overexpression as shown by western blotting, apoptosis-inducing factor (AIF) translocation by immunofluorescence, DNA damage by comet assay, and mitochondrial membrane potential collapse by flow cytometry. These results were ROS-independent. Furthermore, ZINC253504760 is an ATP-competitive MEK inhibitor evidenced by its interaction with the MEK phosphorylation site as shown by molecular docking in silico and binding to recombinant MEK by microscale thermophoresis in vitro. To the best of our knowledge, this is the first time to describe a cardenolide that induces parthanatos in leukemia cells, which may help to improve efforts to overcome drug resistance in cancer. A cardiac glycoside compound ZINC253504760 displayed cytotoxicity against different multidrug-resistant cell lines. ZINC253504760 exhibited cytotoxicity in CCRF-CEM leukemia cells by predominantly inducing a new mode of cell death (parthanatos). ZINC253504760 downregulated MEK1/2 phosphorylation and further affected ERK activation, which induced G2/M phase arrest.
Date of acceptance
2023
Autoren
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/37322258
DOI
10.1007/s10565-023-09813-w
eISSN
1573-6822
Externe Identifier
  • PubMed Central ID: PMC10693532
Ausgabe der Veröffentlichung
6
Zeitschrift
Cell Biol Toxicol
Schlüsselwörter
  • Cardiac glycosides
  • Leukemia
  • MEK inhibitors
  • Parthanatos
  • Synthetic derivative
  • Transcriptomics
  • Humans
  • Apoptosis
  • Phosphorylation
  • Cell Line, Tumor
  • Cardiac Glycosides
  • Down-Regulation
  • Molecular Docking Simulation
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Parthanatos
  • G2 Phase Cell Cycle Checkpoints
  • Neoplasm Proteins
  • Leukemia
  • Cardenolides
  • Mitogen-Activated Protein Kinase Kinases
  • Drug Resistance, Neoplasm
Sprache
eng
Country
Switzerland
Paginierung
2971 - 2997
PII
10.1007/s10565-023-09813-w
Datum der Veröffentlichung
2023
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2023
Titel
The cardiac glycoside ZINC253504760 induces parthanatos-type cell death and G2/M arrest via downregulation of MEK1/2 phosphorylation in leukemia cells.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
39

Data source: PubMed

Author's licence
CC-BY
Autoren
Hosting institution
Universitätsbibliothek Mainz
Sammlungen
  • DFG-491381577-H
Resource version
Published version
DOI
10.1007/s10565-023-09813-w
Funding acknowledgements
  • Deutsche Forschungsgemeinschaft (DFG)|491381577|Open-Access-Publikationskosten 2022–2024 Universität Mainz - Universitätsmedizin
File(s) embargoed
false
Open access
true
ISSN
1573-6822
Zeitschrift
Cell biology and toxicology
Schlüsselwörter
  • 570 Biowissenschaften
  • 570 Life sciences
Sprache
eng
Open access status
Open Access
Datum der Veröffentlichung
2023
Public URL
https://openscience.ub.uni-mainz.de/handle/20.500.12030/9426
Herausgeber
Springer Science + Business Media B.V.
Datum der Datenerfassung
2023
Datum, an dem der Datensatz öffentlich gemacht wurde
2023
Zugang
Public
Titel
The cardiac glycoside ZINC253504760 induces parthanatos-type cell death and G2/M arrest via downregulation of MEK1/2 phosphorylation in leukemia cells
Ausgabe der Zeitschrift
Version of Record (VoR)

Files

the_cardiac_glycoside_zinc253-20230815154227037.pdf

Data source: OPENSCIENCE.UB

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