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.

Department of Neurobiology Institute for Biological Research University of Belgrade Bulevar Despota Stefana 142 11060 Belgrade Serbia

Graduate Institute of Natural Products Kaohsiung Medical University Shih Chuan 1st Rd 100 Kaohsiung 807 Taiwan ROC

INSERM UMR 1248 IPPRITT Université Limoges Faculty of Pharmacy 2 rue du Dr Marcland F 87000 Limoges France

Institute of Medical Microbiology and Immunobiology Faculty of Medicine University of Szeged Dóm tér 10 H 6720 Szeged Hungary

RCPTM Faculty of Sciences Palacký University tr 17 listopadu 12 771 46 Olomouc Czech Republic

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