Antioxidant-Inspired Drug Discovery: Antitumor Metabolite Is Formed in Situ from a Hydroxycinnamic Acid Derivative upon Free-Radical Scavenging
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Drug Resistance, Neoplasm drug effects MeSH
- Cyclohexanones pharmacology toxicity MeSH
- Hydroxyl Radical chemistry MeSH
- Coumaric Acids chemistry metabolism pharmacology MeSH
- Humans MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Drug Discovery MeSH
- Oxidation-Reduction MeSH
- Computer Simulation MeSH
- DNA Damage drug effects MeSH
- Antineoplastic Agents pharmacology toxicity MeSH
- Free Radical Scavengers pharmacology toxicity MeSH
- Signal Transduction drug effects MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 4-coumaric acid methyl ester MeSH Browser
- Cyclohexanones MeSH
- Hydroxyl Radical MeSH
- Coumaric Acids MeSH
- Antineoplastic Agents MeSH
- Free Radical Scavengers MeSH
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.
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