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

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.