Artesunate Derived from Traditional Chinese Medicine Induces DNA Damage and Repair

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 ;-H2AX, which is considered to be an indication of DNA double-strand breaks (DSB). Polymerase B-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 endjoining (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]

Synergism of Cytotoxicity Effects of Triptolide and Artesunate Combination Treatment in Pancreatic Cancer Cell Lines

“…It's over expression is associated to antiapoptosis property and chemotherapy resistance in a variety of tumors including prostate, breast, gastric, and colon cancers. Newly reports have shown that these heat shock proteins may be act as a target for anti-tumor therapy (Li et al, 2008;Du et al, 2010). In the present study, we found that HSP20 and HSP27 declined during combination.…”

Dihydroartemisinin Induces Apoptosis by a Bak-Dependent Intrinsic Pathway

“…This observation is reminiscent of artemisinin-induced oxidative membrane damage in P. falciparum (4). However, the induction of oxidative membrane damage is a completely novel facet of the antineoplastic DHA action that up to now had solely been attributed to DNA damage (46).…”

Artesunate inhibits growth and induces apoptosis in human osteosarcoma HOS cell line in vitro and in vivo

“…In addition, Berger et al (2005) first reported that long-term treatment with ART in combination with standard chemotherapy prolonged the survival time of two cancer patients suffering from metastatic uveal melanoma. Possible mechanisms for the antitumour activity of ART include induction of tumour cell apoptosis or oncosis (Efferth et al, 2007;Li et al, 2009;Du et al, 2010), inhibition of angiogenesis and downregulation of vascular endothelial growth factor expression (Dell′Eva et al, 2004;Zhou et al, 2007), induction of DNA damage (Li et al, 2008), suppression of the hyperactive Wnt/β-catenin pathway , and inhibition of tumour invasion and metastasis (Rasheed et al, 2010). Apart from these, Efferth et al (2003) reported that oxidative stress, which seems to be necessary for the antimalarial effects of ART, also plays an important role in ART antitumour activity.…”