Wedelolactone is one of the active plant polyphenolic compounds. Anti-tumor effects of this drug have been demonstrated recently. We have described that wedelolactone acts as catalytic inhibitor of DNA topoisomerase IIα. The aim of this study was to further characterize the mechanism of its anti-tumor effects. We showed that wedelolactone inhibits binding of DNA topoisomerase IIα to plasmid DNA and antagonizes formation of etoposide-induced DNA cleavage complex. The inhibition of topoisomerase IIα by wedelolactone is reversible by excess of the enzyme but not DNA. The in vitro inhibitory effect of wedelolactone on the topoisomerase IIα activity is redox-dependent as it diminished in the presence of reducing agents. Cytotoxicity of wedelolactone was partially inhibited by N-acetylcysteine and glutathione ethyl ester in breast cancer MDA-MB-231 and MDA-MB-468 cells while the inhibitory effect of catalase was observed only in the former cell line. Finally, we found that wedelolactone can be oxidized in the presence of copper ions resulting in DNA strand break and abasic site formation in vitro. However, wedelolactone induced neither DNA damage in MDA-MB-231 cells nor mutations in bacterial cells detectable by Ames test suggesting that wedelolactone may not be an effective inducer of DNA damage. We conclude that the topoisomerase IIα inhibitory- and DNA damaging activities of wedelolactone in vitro depend on its redox state. Pro-oxidant activity could, however, explain only part of wedelolactone-induced cytotoxicity. Therefore, the major cellular target(s) of wedelolactone and the exact mechanism of wedelolactone-induced cytotoxicity still remain to be identified.
- MeSH
- acetylcystein MeSH
- antigeny nádorové metabolismus MeSH
- DNA vazebné proteiny antagonisté a inhibitory metabolismus MeSH
- DNA-topoisomerasy typu II metabolismus MeSH
- glutathion analogy a deriváty MeSH
- imunoblotting MeSH
- katalasa MeSH
- kumariny chemie metabolismus farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- NAD metabolismus MeSH
- nádorové buněčné linie MeSH
- nádory prsu farmakoterapie MeSH
- oxidace-redukce MeSH
- protinádorové látky chemie metabolismus farmakologie MeSH
- techniky in vitro MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- experimenty na zvířatech MeSH
- financování organizované MeSH
- glutathion analogy a deriváty metabolismus MeSH
- kadmium farmakologie metabolismus MeSH
- kurkumin farmakologie metabolismus MeSH
- potkani Wistar MeSH
- selen farmakologie metabolismus MeSH
- stilbeny farmakologie metabolismus MeSH
- thioredoxinreduktasa 1 metabolismus účinky léků MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- abstrakty MeSH
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- antioxidancia klasifikace metabolismus MeSH
- ateroskleróza * komplikace prevence a kontrola MeSH
- diabetes mellitus metabolismus prevence a kontrola MeSH
- experimenty na zvířatech MeSH
- financování organizované MeSH
- glutathion * analogy a deriváty metabolismus terapeutické užití MeSH
- hypertriglyceridemie farmakoterapie komplikace krev MeSH
- inzulinová rezistence MeSH
- kardiovaskulární nemoci metabolismus prevence a kontrola MeSH
- krysa rodu rattus MeSH
- oxidační stres * účinky léků MeSH
- spektrofotometrie metody využití MeSH
- statistika jako téma MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
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- časové faktory MeSH
- gama-glutamyltransferasa metabolismus MeSH
- glutathion analogy a deriváty metabolismus MeSH
- malondialdehyd metabolismus MeSH
- myokard metabolismus MeSH
- psi MeSH
- reperfuzní poškození myokardu diagnóza metabolismus MeSH
- srdeční komory mikrobiologie MeSH
- zvířata MeSH
- Check Tag
- psi MeSH
- zvířata MeSH
- MeSH
- glutathion analogy a deriváty metabolismus MeSH
- lidé MeSH
- tkáně fyziologie MeSH
- Check Tag
- lidé MeSH
