Effect of artemisinins and other endoperoxides on nitric oxide-related signaling pathway in RAW 264.7 mouse macrophage cells

Autoren

V Badireenath Konkimalla
Martina Blunder
Bernhard Korn
Shahid A Soomro
Herwig Jansen
Wonsuk Chang
Gary H Posner
Rudolf Bauer
Thomas Efferth

DOI

10.1016/j.niox.2008.04.008

ISSN

1089-8603

Ausgabe der Veröffentlichung

2

Zeitschrift

Nitric Oxide

Sprache

en

Paginierung

184 - 191

Datum der Veröffentlichung

2008

Status

Published

Herausgeber

Elsevier BV

Herausgeber URL

http://dx.doi.org/10.1016/j.niox.2008.04.008

Datum der Datenerfassung

2023

Titel

Effect of artemisinins and other endoperoxides on nitric oxide-related signaling pathway in RAW 264.7 mouse macrophage cells

Ausgabe der Zeitschrift

19

Data source: Crossref

Abstract

Artemisinin is the active principle of the Chinese herb Artemisia annua L. In addition to its anti-malarial activity, artemisinin and its derivatives have been shown to exert profound anti-cancer activity. The endoperoxide moiety in the chemical structure of artemisinin is thought to be responsible for the bioactivity. Here, we analyzed the cytotoxicity and the ability of artemisinin, five of its derivatives, and two other endoperoxides to inhibit generation of nitric oxide (NO). In the RAW 264.7 mouse macrophage cell line, the well-established model cell line to analyze NO generation, artesunate revealed the highest ability to inhibit NO production among all compounds tested. In cytotoxicity assays (XTT assay), the IC(50) value of RAW 264.7 cells for artesunate was determined to be 3.1+/-0.7 microM. In order to associate the cytotoxic effects with specific alteration in gene expression related to NO metabolism and signaling, whole genome mRNA microarray analyses were conducted. RAW 264.7 cells were treated with artesunate using DMSO as vehicle control followed by microarray analysis. A total of 36 genes related to NO metabolism and signaling were found to be differentially expressed upon exposure to artesunate. Apart from NO-related genes, the expression of genes associated with other functional groups was also analyzed. Out of 24 functional groups, differential expression was most prominent in genes involved in cell-to-cell signaling and interactions. Further refinement of this analysis showed that the pathways for cAMP-mediated signaling and Wnt/beta-catenin signaling were most closely related to changes in mRNA expression. In conclusion, NO generation and signaling play a role in exhibiting cytotoxic activity of artesunate. In addition, other signaling pathways also contribute to the inhibitory effect of artesunate towards RAW 264.7 cells pointing to a multi-factorial mode of action of artesunate.

Addresses

German Cancer Research Center, Pharmaceutical Biology (C015), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.

Autoren

V Badireenath Konkimalla
Martina Blunder
Bernhard Korn
Shahid A Soomro
Herwig Jansen
Wonsuk Chang
Gary H Posner
Rudolf Bauer
Thomas Efferth
Thomas Efferth

DOI

10.1016/j.niox.2008.04.008

eISSN

1089-8611

Externe Identifier

PubMed Identifier: 18472018
PubMed Central ID: PMC2582405

Funding acknowledgements

NIAID NIH HHS: R37 AI034885
NIAID NIH HHS: R37 AI034885-15

Open access

false

ISSN

1089-8603

Ausgabe der Veröffentlichung

2

Zeitschrift

Nitric oxide : biology and chemistry

Schlüsselwörter

Cell Line
Macrophages
Animals
Mice
Peroxides
Nitric Oxide
Artemisinins
Gene Expression Profiling
Cell Communication
Signal Transduction
Cell Death

Sprache

eng

Medium

Print-Electronic

Online publication date

2008

Paginierung

184 - 191

Datum der Veröffentlichung

2008

Status

Published

Datum der Datenerfassung

2008

Titel

Effect of artemisinins and other endoperoxides on nitric oxide-related signaling pathway in RAW 264.7 mouse macrophage cells.

Sub types

Research Support, Non-U.S. Gov't
research-article
Journal Article

Ausgabe der Zeitschrift

19

Files

https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18472018/pdf/?tool=EBI https://europepmc.org/articles/PMC2582405?pdf=render

Data source: Europe PubMed Central

Abstract

Artemisinin is the active principle of the Chinese herb Artemisia annua L. In addition to its anti-malarial activity, artemisinin and its derivatives have been shown to exert profound anti-cancer activity. The endoperoxide moiety in the chemical structure of artemisinin is thought to be responsible for the bioactivity. Here, we analyzed the cytotoxicity and the ability of artemisinin, five of its derivatives, and two other endoperoxides to inhibit generation of nitric oxide (NO). In the RAW 264.7 mouse macrophage cell line, the well-established model cell line to analyze NO generation, artesunate revealed the highest ability to inhibit NO production among all compounds tested. In cytotoxicity assays (XTT assay), the IC(50) value of RAW 264.7 cells for artesunate was determined to be 3.1+/-0.7 microM. In order to associate the cytotoxic effects with specific alteration in gene expression related to NO metabolism and signaling, whole genome mRNA microarray analyses were conducted. RAW 264.7 cells were treated with artesunate using DMSO as vehicle control followed by microarray analysis. A total of 36 genes related to NO metabolism and signaling were found to be differentially expressed upon exposure to artesunate. Apart from NO-related genes, the expression of genes associated with other functional groups was also analyzed. Out of 24 functional groups, differential expression was most prominent in genes involved in cell-to-cell signaling and interactions. Further refinement of this analysis showed that the pathways for cAMP-mediated signaling and Wnt/beta-catenin signaling were most closely related to changes in mRNA expression. In conclusion, NO generation and signaling play a role in exhibiting cytotoxic activity of artesunate. In addition, other signaling pathways also contribute to the inhibitory effect of artesunate towards RAW 264.7 cells pointing to a multi-factorial mode of action of artesunate.

Date of acceptance

2008

Autoren

V Badireenath Konkimalla
Martina Blunder
Bernhard Korn
Shahid A Soomro
Herwig Jansen
Wonsuk Chang
Gary H Posner
Rudolf Bauer
Thomas Efferth

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/18472018

DOI

10.1016/j.niox.2008.04.008

eISSN

1089-8611

Externe Identifier

NIH Manuscript Submission ID: NIHMS76090
PubMed Central ID: PMC2582405

Funding acknowledgements

NIAID NIH HHS: R37 AI034885
NIAID NIH HHS: R37 AI034885-15

Ausgabe der Veröffentlichung

2

Zeitschrift

Nitric Oxide

Schlüsselwörter

Animals
Artemisinins
Cell Communication
Cell Death
Cell Line
Gene Expression Profiling
Macrophages
Mice
Nitric Oxide
Peroxides
Signal Transduction

Sprache

eng

Country

United States

Paginierung

184 - 191

PII

S1089-8603(08)00051-7

Datum der Veröffentlichung

2008

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2008

Titel

Effect of artemisinins and other endoperoxides on nitric oxide-related signaling pathway in RAW 264.7 mouse macrophage cells.

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

19

Data source: PubMed

Effect of artemisinins and other endoperoxides on nitric oxide-related signaling pathway in RAW 264.7 mouse macrophage cells

Files

Tools