Antioxidant-Inspired Drug Discovery: Antitumor Metabolite Is Formed in Situ from a Hydroxycinnamic Acid Derivative upon Free-Radical Scavenging.

Abstract

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.

• Authors: Laura Fási, Florent Di Meo, Ching-Ying Kuo, Sonja Stojkovic Buric, Ana Martins, Norbert Kúsz, Zoltán Béni, Miklós Dékány, György Tibor Balogh, Milica Pesic, Hui-Chun Wang, Patrick Trouillas, Attila Hunyadi
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 62 Issue 3 Pg. 1657-1668 (02 14 2019) ISSN: 1520-4804 [Electronic] United States
• PMID: 30615450 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Coumaric Acids
• Cyclohexanones
• Free Radical Scavengers
• Hydroxyl Radical
• 4-coumaric acid methyl ester

Topics

• Animals
• Antineoplastic Agents (pharmacology, toxicity)
• Cell Line, Tumor
• Computer Simulation
• Coumaric Acids (chemistry, metabolism, pharmacology)
• Cyclohexanones (pharmacology, toxicity)
• DNA Damage (drug effects)
• Drug Discovery
• Drug Resistance, Neoplasm (drug effects)
• Free Radical Scavengers (pharmacology, toxicity)
• Humans
• Hydroxyl Radical (chemistry)
• Mice
• Oxidation-Reduction
• Signal Transduction (drug effects)