123064-80-2Relevant articles and documents
Antioxidant-Inspired Drug Discovery: Antitumor Metabolite Is Formed in Situ from a Hydroxycinnamic Acid Derivative upon Free-Radical Scavenging
Fási, Laura,Di Meo, Florent,Kuo, Ching-Ying,Stojkovic Buric, Sonja,Martins, Ana,Kúsz, Norbert,Béni, Zoltán,Dékány, Miklós,Balogh, Gy?rgy Tibor,Pesic, Milica,Wang, Hui-Chun,Trouillas, Patrick,Hunyadi, Attila
, p. 1657 - 1668 (2019/02/24)
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.
