Artesunate derived from traditional Chinese medicine induces DNA damage and repair

Abstract

Abstract Artesunate is a semisynthetic derivative from artemisinin, a natural product from the Chinese herb Artemisia annua L. It exerts antimalarial activity, and, additionally, artemisinin and its derivatives are active against cancer cells. The active moiety is an endoperoxide bridge. Its cleavage leads to the formation of reactive oxygen species and carbon-centered radicals. These highly reactive molecules target several proteins in Plasmodia, which is thought to result in killing of the microorganism. DNA damage induced by artemisinins has not yet been described. Here, we show that artesunate induces apoptosis and necrosis. It also induces DNA breakage in a dose-dependent manner as shown by single-cell gel electrophoresis. This genotoxic effect was confirmed by measuring the level of γ-H2AX, which is considered to be an indication of DNA double-strand breaks (DSB). Polymerase β–deficient cells were more sensitive than the wild-type to artesunate, indicating that the drug induces DNA damage that is repaired by base excision repair. irs1 and VC8 cells defective in homologous recombination (HR) due to inactivation of XRCC2 and BRCA2, respectively, were more sensitive to artesunate than the corresponding wild-type. This was also true for XR-V15B cells defective in nonhomologous end-joining (NHEJ) due to inactivation of Ku80. The data indicate that DSBs induced by artesunate are repaired by the HR and NHEJ pathways. They suggest that DNA damage induced by artesunate contributes to its therapeutic effect against cancer cells. [Cancer Res 2008;68(11):4347–51]

Autoren

Paul CH Li
Elena Lam
Wynand P Roos
Małgorzata Z Zdzienicka
Bernd Kaina
Thomas Efferth

DOI

10.1158/0008-5472.can-07-2970

eISSN

1538-7445

ISSN

0008-5472

Ausgabe der Veröffentlichung

11

Zeitschrift

Cancer Research

Sprache

en

Online publication date

2008

Paginierung

4347 - 4351

Datum der Veröffentlichung

2008

Status

Published

Herausgeber

American Association for Cancer Research (AACR)

Herausgeber URL

http://dx.doi.org/10.1158/0008-5472.can-07-2970

Datum der Datenerfassung

2022

Titel

Artesunate Derived from Traditional Chinese Medicine Induces DNA Damage and Repair

Ausgabe der Zeitschrift

68

Data source: Crossref

Abstract

Artesunate is a semisynthetic derivative from artemisinin, a natural product from the Chinese herb Artemisia annua L. It exerts antimalarial activity, and, additionally, artemisinin and its derivatives are active against cancer cells. The active moiety is an endoperoxide bridge. Its cleavage leads to the formation of reactive oxygen species and carbon-centered radicals. These highly reactive molecules target several proteins in Plasmodia, which is thought to result in killing of the microorganism. DNA damage induced by artemisinins has not yet been described. Here, we show that artesunate induces apoptosis and necrosis. It also induces DNA breakage in a dose-dependent manner as shown by single-cell gel electrophoresis. This genotoxic effect was confirmed by measuring the level of gamma-H2AX, which is considered to be an indication of DNA double-strand breaks (DSB). Polymerase beta-deficient cells were more sensitive than the wild-type to artesunate, indicating that the drug induces DNA damage that is repaired by base excision repair. irs1 and VC8 cells defective in homologous recombination (HR) due to inactivation of XRCC2 and BRCA2, respectively, were more sensitive to artesunate than the corresponding wild-type. This was also true for XR-V15B cells defective in nonhomologous end-joining (NHEJ) due to inactivation of Ku80. The data indicate that DSBs induced by artesunate are repaired by the HR and NHEJ pathways. They suggest that DNA damage induced by artesunate contributes to its therapeutic effect against cancer cells.

Addresses

Institute of Toxicology, University of Mainz, Mainz, Germany.

Autoren

Paul CH Li
Elena Lam
Wynand P Roos
Malgorzata Z Zdzienicka
Bernd Kaina
Thomas Efferth
Thomas Efferth

DOI

10.1158/0008-5472.can-07-2970

eISSN

1538-7445

Externe Identifier

PubMed Identifier: 18519695

Open access

false

ISSN

0008-5472

Ausgabe der Veröffentlichung

11

Zeitschrift

Cancer research

Schlüsselwörter

Cell Line
Animals
Cricetulus
DNA Damage
Artemisinins
DNA
Fluorescent Antibody Technique
Blotting, Western
Medicine, Chinese Traditional
Comet Assay
Apoptosis
DNA Repair
Cricetinae
Artesunate

Sprache

eng

Medium

Print

Paginierung

4347 - 4351

Datum der Veröffentlichung

2008

Status

Published

Datum der Datenerfassung

2008

Titel

Artesunate derived from traditional Chinese medicine induces DNA damage and repair.

Sub types

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

Ausgabe der Zeitschrift

68

Data source: Europe PubMed Central

Abstract

Artesunate is a semisynthetic derivative from artemisinin, a natural product from the Chinese herb Artemisia annua L. It exerts antimalarial activity, and, additionally, artemisinin and its derivatives are active against cancer cells. The active moiety is an endoperoxide bridge. Its cleavage leads to the formation of reactive oxygen species and carbon-centered radicals. These highly reactive molecules target several proteins in Plasmodia, which is thought to result in killing of the microorganism. DNA damage induced by artemisinins has not yet been described. Here, we show that artesunate induces apoptosis and necrosis. It also induces DNA breakage in a dose-dependent manner as shown by single-cell gel electrophoresis. This genotoxic effect was confirmed by measuring the level of gamma-H2AX, which is considered to be an indication of DNA double-strand breaks (DSB). Polymerase beta-deficient cells were more sensitive than the wild-type to artesunate, indicating that the drug induces DNA damage that is repaired by base excision repair. irs1 and VC8 cells defective in homologous recombination (HR) due to inactivation of XRCC2 and BRCA2, respectively, were more sensitive to artesunate than the corresponding wild-type. This was also true for XR-V15B cells defective in nonhomologous end-joining (NHEJ) due to inactivation of Ku80. The data indicate that DSBs induced by artesunate are repaired by the HR and NHEJ pathways. They suggest that DNA damage induced by artesunate contributes to its therapeutic effect against cancer cells.

Autoren

Paul CH Li
Elena Lam
Wynand P Roos
Malgorzata Z Zdzienicka
Bernd Kaina
Thomas Efferth

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/18519695

DOI

10.1158/0008-5472.CAN-07-2970

eISSN

1538-7445

Ausgabe der Veröffentlichung

11

Zeitschrift

Cancer Res

Schlüsselwörter

Animals
Apoptosis
Artemisinins
Artesunate
Blotting, Western
Cell Line
Comet Assay
Cricetinae
Cricetulus
DNA
DNA Damage
DNA Repair
Fluorescent Antibody Technique
Medicine, Chinese Traditional

Sprache

eng

Country

United States

Paginierung

4347 - 4351

PII

68/11/4347

Datum der Veröffentlichung

2008

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2008

Titel

Artesunate derived from traditional Chinese medicine induces DNA damage and repair.

Sub types

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

Ausgabe der Zeitschrift

68

Data source: PubMed

Artesunate derived from traditional Chinese medicine induces DNA damage and repair

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