Artesunate derived from traditional Chinese medicine induces DNA damage and repair.
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.
Li
Paul C H
PC
Institute of Toxicology, University of Mainz, Mainz, Germany.
Lam
Elena
E
Roos
Wynand P
WP
Zdzienicka
Malgorzata Z
MZ
Kaina
Bernd
B
Efferth
Thomas
T
D000818:Animals; D017209:Apoptosis; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D015153:Blotting, Western; D002460:Cell Line; D020552:Comet Assay; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D004260:DNA Repair; D005455:Fluorescent Antibody Technique; D008516:Medicine, Chinese Traditional
D037621:Artemisinins; D000077332:Artesunate; D004247:DNA