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

Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-9408

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DC Field	Value	Language
dc.contributor.author	Zhou, Min	-
dc.contributor.author	Boulos, Joelle C.	-
dc.contributor.author	Klauck, Sabine M.	-
dc.contributor.author	Efferth, Thomas	-
dc.date.accessioned	2023-08-24T08:31:49Z	-
dc.date.available	2023-08-24T08:31:49Z	-
dc.date.issued	2023	-
dc.identifier.uri	https://openscience.ub.uni-mainz.de/handle/20.500.12030/9426	-
dc.description.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.	en_GB
dc.description.sponsorship	Deutsche Forschungsgemeinschaft (DFG)\|491381577\|Open-Access-Publikationskosten 2022–2024 Universität Mainz - Universitätsmedizin	-
dc.language.iso	eng	de
dc.rights	CC BY	*
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/	*
dc.subject.ddc	570 Biowissenschaften	de_DE
dc.subject.ddc	570 Life sciences	en_GB
dc.title	The cardiac glycoside ZINC253504760 induces parthanatos-type cell death and G2/M arrest via downregulation of MEK1/2 phosphorylation in leukemia cells	en_GB
dc.type	Zeitschriftenaufsatz	de
dc.identifier.doi	http://doi.org/10.25358/openscience-9408	-
jgu.type.dinitype	article	en_GB
jgu.type.version	Published version	de
jgu.type.resource	Text	de
jgu.organisation.department	FB 09 Chemie, Pharmazie u. Geowissensch.	de
jgu.organisation.number	7950	-
jgu.organisation.name	Johannes Gutenberg-Universität Mainz	-
jgu.rights.accessrights	openAccess	-
jgu.journal.title	Cell biology and toxicology	de
jgu.journal.volume	Version of Record (VoR)	de
jgu.publisher.year	2023	-
jgu.publisher.name	Springer Science + Business Media B.V.	de
jgu.publisher.place	Dordrecht	de
jgu.publisher.issn	1573-6822	de
jgu.organisation.place	Mainz	-
jgu.subject.ddccode	570	de
jgu.publisher.doi	10.1007/s10565-023-09813-w	de
jgu.organisation.ror	https://ror.org/023b0x485	-
Appears in collections:	DFG-491381577-H

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