Antioxidant-Inspired Drug Discovery: Antitumor Metabolite Is Formed in Situ from a Hydroxycinnamic Acid Derivative upon Free-Radical Scavenging.
Fási L, Di Meo F, Kuo CY, Stojkovic Buric S, Martins A, Kúsz N, Béni Z, Dékány M, Balogh GT, Pesic M, Wang HC, Trouillas P, Hunyadi A.
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 H<sub>2</sub>O<sub>2</sub>-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 <sup>•</sup>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.