Cancer cells generally possess higher levels of reactive oxygen species than normal cells, and this can serve as a possible therapeutic target. In this proof-of-concept study, an antioxidant-inspired drug discovery strategy was evaluated using a hydroxycinnamic acid derivative. The processing of oxidized mixtures of p-coumaric acid methyl ester (pcm) revealed a new antitumor lead, graviquinone. Graviquinone bypassed ABCB1-mediated resistance, induced DNA damage in lung carcinoma cells but exerted DNA protective activity in normal keratinocytes, and modulated DNA damage response in MCF-7 cells. The cytotoxic effect of pcm in MCF-7 cells was potentiated under H2O2-induced oxidative stress, and the formation of graviquinone was confirmed by Fenton's reaction on pcm. In silico density functional theory calculations suggested graviquinone as a kinetic product of pcm-scavenging •OH radicals. Our results demonstrate the pharmacological value of an in situ-formed, oxidative stress-related metabolite of an antioxidant. This might be of particular importance for designing new strategies for antioxidant-based drug discovery.
- MeSH
- antitumorózní látky farmakologie toxicita MeSH
- chemorezistence účinky léků MeSH
- cyklohexanony farmakologie toxicita MeSH
- hydroxylový radikál chemie MeSH
- kyseliny kumarové chemie metabolismus farmakologie MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- objevování léků MeSH
- oxidace-redukce MeSH
- počítačová simulace MeSH
- poškození DNA účinky léků MeSH
- scavengery volných radikálů farmakologie toxicita MeSH
- signální transdukce účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
