Antioxidant-Inspired Drug Discovery: Antitumor Metabolite Is Formed in Situ from a Hydroxycinnamic Acid Derivative upon Free-Radical Scavenging.
Laura FásiFlorent Di MeoChing-Ying KuoSonja Stojkovic BuricAna MartinsNorbert KúszZoltán BéniMiklós DékányGyörgy Tibor BaloghMilica PesicHui-Chun WangPatrick TrouillasAttila HunyadiPublished in: Journal of medicinal chemistry (2019)
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.
Keyphrases
- drug discovery
- oxidative stress
- induced apoptosis
- dna damage
- density functional theory
- diabetic rats
- cell cycle arrest
- reactive oxygen species
- anti inflammatory
- hydrogen peroxide
- molecular dynamics
- endoplasmic reticulum stress
- signaling pathway
- ischemia reperfusion injury
- dna repair
- cell proliferation
- breast cancer cells
- cell free
- high glucose
- wastewater treatment
- endothelial cells
- molecular docking
- drug induced
- low density lipoprotein
- heat stress
- stress induced