title: Two dietary polyphenols, fisetin and luteolin, reduce inflammation but augment DNA damage-induced toxicity in human RPE cells.
abstract: Plant-derived polyphenols are known to possess anti-inflammatory and antioxidant effects. In recent years, several studies have investigated their potential benefits for treating chronic diseases associated with prolonged inflammation and excessive oxidative stress, such as age-related macular degeneration (AMD). Previously, two polyphenols, fisetin and luteolin, have been reported to increase the survival of retinal pigment epithelial (RPE) cells suffering from oxidative stress as well as decreasing inflammation but the benefits of polyphenol therapy seem to depend on the model system used. Our aim was to analyze the effects of fisetin and luteolin on inflammation and cellular viability in a model of nonoxidative DNA damage-induced cell death in human RPE (hRPE) cells. Pretreatment of ARPE-19 or primary hRPE cells with the polyphenols augmented etoposide-induced cell death as measured by the lactate dehydrogenase and 3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. However, the treatment was able to reduce the release of two proinflammatory cytokines, IL-6 and IL-8, which were determined by enzyme-linked Immunosorbent assay. Analyses of caspase 3 activity, p53 acetylation and SIRT1 protein levels revealed the apoptotic nature of etoposide-evoked cell death and that fisetin and luteolin augmented the etoposide-induced acetylation of p53 and decreased SIRT1 levels. Taken together, our findings suggest that the cytoprotective effects of fisetin and luteolin depend on the stressor they need to combat, whereas their anti-inflammatory potential is sustained over a variety of model systems. Careful consideration of disease pathways will be necessary before fisetin or luteolin can be recommended as therapeutic agents for inflammatory diseases in general and specifically AMD.
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland; Department of Ophthalmology, School of Medicine, University of Eastern Finland, Kuopio, Finland. Electronic address: maria.hytti@uef.fi.
authors.forename: Maria
authors.initials: M
authors.lastname: Hytti
authors.affiliation: Stem Cells and Eye Research Laboratory, Department of Ophthalmology, Faculty of Medicine, University of Szeged, Szeged, Hungary. Electronic address: szabo.julia.dora@gmail.com.
authors.forename: Dora
authors.initials: D
authors.lastname: Szabó
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland; Department of Ophthalmology, School of Medicine, University of Eastern Finland, Kuopio, Finland. Electronic address: niina.e.laakso@uef.fi.
authors.forename: Niina
authors.initials: N
authors.lastname: Piippo
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland; Department of Ophthalmology, School of Medicine, University of Eastern Finland, Kuopio, Finland. Electronic address: eveliina.korhonen@uef.fi.
authors.forename: Eveliina
authors.initials: E
authors.lastname: Korhonen
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland. Electronic address: paavo.honkakoski@uef.fi.
authors.forename: Paavo
authors.initials: P
authors.lastname: Honkakoski
authors.affiliation: Department of Ophthalmology, School of Medicine, University of Eastern Finland, Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland. Electronic address: kai.kaarniranta@uef.fi.
authors.forename: Kai
authors.initials: K
authors.lastname: Kaarniranta
authors.affiliation: Stem Cells and Eye Research Laboratory, Department of Ophthalmology, Faculty of Medicine, University of Szeged, Szeged, Hungary; Center of Eye Research, Department of Ophthalmology, and Norwegian Center for Stem Cell Research, Oslo University Hospital, University of Oslo, Oslo, Norway. Electronic address: goran.petrovski@medisin.uio.no.
authors.forename: Goran
authors.initials: G
authors.lastname: Petrovski
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland. Electronic address: anu.kauppinen@uef.fi.
authors.forename: Anu
authors.initials: A
authors.lastname: Kauppinen
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D019587:Dietary Supplements; D005047:Etoposide / Q000009:adverse effects; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D006801:Humans; D047311:Luteolin / Q000494:pharmacology*; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012173:Retinitis / Q000188:drug therapy; D056564:Sirtuin 1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D005419:Flavonoids; D044948:Flavonols; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D047311:Luteolin; C017875:fisetin
keywords: Age-related macular degeneration; DNA damage; Dietary polyphenols; Fisetin; Inflammation; Luteolin