Jozimine A2, a Dimeric Naphthylisoquinoline (NIQ) Alkaloid, Shows In Vitro Cytotoxic Effects against Leukemia Cells through NF-κB Inhibition

Abstract

Naphthylisoquinoline (NIQ) alkaloids are rising as a promising class of secondary metabolites with pharmaceutical potential. NF-κB has already been recognized as a significant modulator of cancer proliferation and drug resistance. We have previously reported the mechanisms behind the cytotoxic effect of dioncophylline A, an NIQ monomer, in leukemia cells. In the current study, we have investigated the cytotoxic effect of jozimine A2, an NIQ dimer, on leukemia cells in comparison to a second, structurally unsymmetric dimer, michellamine B. To this end, molecular docking was applied to predict the binding affinity of the dimers towards NF-κB, which was then validated through microscale thermophoresis. Next, cytotoxicity assays were performed on CCRF-CEM cells and multidrug-resistant CEM/ADR5000 cells following treatment. Transcriptome analysis uncovered the molecular networks affected by jozimine A2 and identified the cell cycle as one of the major affected processes. Cell death modes were evaluated through flow cytometry, while angiogenesis was measured with the endothelial cell tube formation assay on human umbilical vein endothelial cells (HUVECs). The results indicated that jozimine A2 bound to NF-κB, inhibited its activity and prevented its translocation to the nucleus. In addition, jozimine A2 induced cell death through apoptosis and prevented angiogenesis. Our study describes the cytotoxic effect of jozimine A2 on leukemia cells and explains the interactions with the NF-κB signaling pathway and the anticancer activity.

Autoren

Roxana Damiescu
Rümeysa Yücer
Sabine M Klauck
Gerhard Bringmann
Thomas Efferth
Mona Dawood

DOI

10.3390/ijms25063087

eISSN

1422-0067

Ausgabe der Veröffentlichung

6

Zeitschrift

International Journal of Molecular Sciences

Sprache

en

Online publication date

2024

Paginierung

3087 - 3087

Status

Published online

Herausgeber

MDPI AG

Herausgeber URL

http://dx.doi.org/10.3390/ijms25063087

Datum der Datenerfassung

2024

Titel

Jozimine A2, a Dimeric Naphthylisoquinoline (NIQ) Alkaloid, Shows In Vitro Cytotoxic Effects against Leukemia Cells through NF-κB Inhibition

Ausgabe der Zeitschrift

25

Data source: Crossref

Abstract

Naphthylisoquinoline (NIQ) alkaloids are rising as a promising class of secondary metabolites with pharmaceutical potential. NF-κB has already been recognized as a significant modulator of cancer proliferation and drug resistance. We have previously reported the mechanisms behind the cytotoxic effect of dioncophylline A, an NIQ monomer, in leukemia cells. In the current study, we have investigated the cytotoxic effect of jozimine A2, an NIQ dimer, on leukemia cells in comparison to a second, structurally unsymmetric dimer, michellamine B. To this end, molecular docking was applied to predict the binding affinity of the dimers towards NF-κB, which was then validated through microscale thermophoresis. Next, cytotoxicity assays were performed on CCRF-CEM cells and multidrug-resistant CEM/ADR5000 cells following treatment. Transcriptome analysis uncovered the molecular networks affected by jozimine A2 and identified the cell cycle as one of the major affected processes. Cell death modes were evaluated through flow cytometry, while angiogenesis was measured with the endothelial cell tube formation assay on human umbilical vein endothelial cells (HUVECs). The results indicated that jozimine A2 bound to NF-κB, inhibited its activity and prevented its translocation to the nucleus. In addition, jozimine A2 induced cell death through apoptosis and prevented angiogenesis. Our study describes the cytotoxic effect of jozimine A2 on leukemia cells and explains the interactions with the NF-κB signaling pathway and the anticancer activity.

Addresses

Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.

Autoren

Roxana Damiescu
Rümeysa Yücer
Sabine M Klauck
Gerhard Bringmann
Thomas Efferth
Mona Dawood

DOI

10.3390/ijms25063087

eISSN

1422-0067

Externe Identifier

PubMed Identifier: 38542061
PubMed Central ID: PMC10970593

Funding acknowledgements

Deutsche Forschungsgemeinschaft: GRK2015/2

Open access

true

ISSN

1422-0067

Ausgabe der Veröffentlichung

6

Zeitschrift

International journal of molecular sciences

Schlüsselwörter

Cell Line, Tumor
Endothelial Cells
Humans
Leukemia
Alkaloids
NF-kappa B
Antineoplastic Agents
Apoptosis
Drug Resistance, Neoplasm
Molecular Docking Simulation

Sprache

eng

Medium

Electronic

Online publication date

2024

Open access status

Open Access

Paginierung

3087

Datum der Veröffentlichung

2024

Status

Published

Publisher licence

CC BY

Datum der Datenerfassung

2024

Titel

Jozimine A2, a Dimeric Naphthylisoquinoline (NIQ) Alkaloid, Shows In Vitro Cytotoxic Effects against Leukemia Cells through NF-κB Inhibition.

Sub types

research-article
Journal Article

Ausgabe der Zeitschrift

25

Files

https://europepmc.org/articles/PMC10970593?pdf=render

Data source: Europe PubMed Central

Abstract

Naphthylisoquinoline (NIQ) alkaloids are rising as a promising class of secondary metabolites with pharmaceutical potential. NF-κB has already been recognized as a significant modulator of cancer proliferation and drug resistance. We have previously reported the mechanisms behind the cytotoxic effect of dioncophylline A, an NIQ monomer, in leukemia cells. In the current study, we have investigated the cytotoxic effect of jozimine A2, an NIQ dimer, on leukemia cells in comparison to a second, structurally unsymmetric dimer, michellamine B. To this end, molecular docking was applied to predict the binding affinity of the dimers towards NF-κB, which was then validated through microscale thermophoresis. Next, cytotoxicity assays were performed on CCRF-CEM cells and multidrug-resistant CEM/ADR5000 cells following treatment. Transcriptome analysis uncovered the molecular networks affected by jozimine A2 and identified the cell cycle as one of the major affected processes. Cell death modes were evaluated through flow cytometry, while angiogenesis was measured with the endothelial cell tube formation assay on human umbilical vein endothelial cells (HUVECs). The results indicated that jozimine A2 bound to NF-κB, inhibited its activity and prevented its translocation to the nucleus. In addition, jozimine A2 induced cell death through apoptosis and prevented angiogenesis. Our study describes the cytotoxic effect of jozimine A2 on leukemia cells and explains the interactions with the NF-κB signaling pathway and the anticancer activity.

Date of acceptance

2024

Autoren

Roxana Damiescu
Rümeysa Yücer
Sabine M Klauck
Gerhard Bringmann
Thomas Efferth
Mona Dawood

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/38542061

DOI

10.3390/ijms25063087

eISSN

1422-0067

Externe Identifier

PubMed Central ID: PMC10970593

Ausgabe der Veröffentlichung

6

Zeitschrift

Int J Mol Sci

Schlüsselwörter

apoptosis
autophagy
jozimine A2
leukemia cells
natural products
transcriptomics
Humans
Alkaloids
Antineoplastic Agents
Apoptosis
Cell Line, Tumor
Drug Resistance, Neoplasm
Endothelial Cells
Leukemia
Molecular Docking Simulation
NF-kappa B

Sprache

eng

Country

Switzerland

PII

ijms25063087

Datum der Veröffentlichung

2024

Status

Published online

Datum, an dem der Datensatz öffentlich gemacht wurde

2024

Titel

Jozimine A2, a Dimeric Naphthylisoquinoline (NIQ) Alkaloid, Shows In Vitro Cytotoxic Effects against Leukemia Cells through NF-κB Inhibition.

Sub types

Journal Article

Ausgabe der Zeitschrift

25

Data source: PubMed

Jozimine A2, a Dimeric Naphthylisoquinoline (NIQ) Alkaloid, Shows In Vitro Cytotoxic Effects against Leukemia Cells through NF-κB Inhibition

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