Abstract
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.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.