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

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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.

Graphical Abstract

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.

Supplementary Information

The online version contains supplementary material available at 10.1007/s10565-023-09813-w.

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Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

Kenneth Livak, Thomas D. Schmittgen (2001)

The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data. Copyright 2001 Elsevier Science (USA).

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Cancer statistics, 2022

Rebecca Siegel, Kimberly D Miller, Hannah Fuchs … (2022)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes. Incidence data (through 2018) were collected by the Surveillance, Epidemiology, and End Results program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2019) were collected by the National Center for Health Statistics. In 2022, 1,918,030 new cancer cases and 609,360 cancer deaths are projected to occur in the United States, including approximately 350 deaths per day from lung cancer, the leading cause of cancer death. Incidence during 2014 through 2018 continued a slow increase for female breast cancer (by 0.5% annually) and remained stable for prostate cancer, despite a 4% to 6% annual increase for advanced disease since 2011. Consequently, the proportion of prostate cancer diagnosed at a distant stage increased from 3.9% to 8.2% over the past decade. In contrast, lung cancer incidence continued to decline steeply for advanced disease while rates for localized-stage increased suddenly by 4.5% annually, contributing to gains both in the proportion of localized-stage diagnoses (from 17% in 2004 to 28% in 2018) and 3-year relative survival (from 21% to 31%). Mortality patterns reflect incidence trends, with declines accelerating for lung cancer, slowing for breast cancer, and stabilizing for prostate cancer. In summary, progress has stagnated for breast and prostate cancers but strengthened for lung cancer, coinciding with changes in medical practice related to cancer screening and/or treatment. More targeted cancer control interventions and investment in improved early detection and treatment would facilitate reductions in cancer mortality.

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PUVA-induced repigmentation of vitiligo: scanning electron microscopy of hair follicles.

J P Ortonne, Björn D Schmitt, J Thivolet (1979)

PUVA-i-duced repigmentation of vitiligo was studied using both the split-dopa reaction and scanning electron microscopy. Proliferation of hypertrophic, Dopa-positive melanocytes were observed in the lower portion of some hair follicles, whereas other giant melanocytes were observed along the middle portion. The existence of a melanocyte reservoir in human hair follicles is postulated.

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Author and article information

Contributors

Thomas Efferth: efferth@uni-mainz.de

Journal

Journal ID (nlm-ta): Cell Biol Toxicol

Journal ID (iso-abbrev): Cell Biol Toxicol

Title: Cell Biology and Toxicology

Publisher: Springer Netherlands (Dordrecht )

ISSN (Print): 0742-2091

ISSN (Electronic): 1573-6822

Publication date (Electronic): 16 June 2023

Publication date PMC-release: 16 June 2023

Publication date (Print): 2023

Volume: 39

Issue: 6

Pages: 2971-2997

Affiliations

[1 ]Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University-Mainz, ( https://ror.org/023b0x485) Staudinger Weg 5, 55128 Mainz, Germany

[2 ]GRID grid.461742.2, ISNI 0000 0000 8855 0365, Division of Cancer Genome Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), , National Center for Tumor Disease (NCT), ; 69120 Heidelberg, Germany

Article

Publisher ID: 9813

DOI: 10.1007/s10565-023-09813-w

PMC ID: 10693532

PubMed ID: 37322258

SO-VID: 6c767187-89d2-4a87-925a-0706f6a889ba

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 23 February 2023

Date accepted : 23 May 2023

Funding

Funded by: Johannes Gutenberg-Universität Mainz (1030)

Open Access :

Open Access funding enabled and organized by Projekt DEAL.

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ScienceOpen disciplines: Cell biology

Keywords: cardiac glycosides,leukemia,mek inhibitors,parthanatos,synthetic derivative,transcriptomics

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ScienceOpen disciplines: Cell biology

Keywords: cardiac glycosides, leukemia, mek inhibitors, parthanatos, synthetic derivative, transcriptomics

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

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Most cited references 112

Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

Cancer statistics, 2022

PUVA-induced repigmentation of vitiligo: scanning electron microscopy of hair follicles.

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