A purified Feverfew extract protects from oxidative damage by inducing DNA repair in skin cells via a PI3-kinase-dependent Nrf2/ARE pathway

Published:September 16, 2013DOI:



      Environmental factors such as solar ultraviolet (UV) radiation and other external aggressors provide an oxidative challenge that is detrimental to skin health. The levels of endogenous antioxidants decrease with age, thus resulting in less protection and a greater potential for skin damage. The NF-E2-related factor-2 (Nrf2) – antioxidant response element (ARE) pathway is a primary defense mechanism against oxidative stress, and induces the expression of antioxidant, detoxification and repair genes. Activation of ARE-Nrf2 can help restore oxidative homeostasis of the skin and play a role in inflammatory response and DNA repair mechanisms.


      To evaluate the role of a purified parthenolide-depleted Feverfew (PD-Feverfew) extract on the ARE-Nrf2 pathway and DNA repair in skin cells.


      These studies were undertaken in primary human keratinocytes or KB cells using Luciferase Promoter assay, siRNA transfection studies, Western blot analyses, Immunofluorescence microscopy, comet assay and quantitative real-time PCR.


      PD-Feverfew was found to induce Nrf2 nuclear translocation and to increase ARE activity in a dose dependent manner. Furthermore, knockdown of Nrf2 resulted in suppression of PD-Feverfew-induced ARE activity. PD-Feverfew was also found to induce phosphorylation of Akt, a kinase downstream of PI3K. Inhibition of PI3K via pre-treatment with the selective pharmacological inhibitor, LY294002, abolished PD-Feverfew-induced Nrf2/ARE activation. PD-Feverfew also reduced UV-induced DNA damage in a PI3K and Nrf2-dependent manner.


      Therefore, by increasing endogenous defense mechanisms and aid in DNA repair of damaged skin cells via activation of a PI3K-dependent Nrf2/ARE pathway, PD-Feverfew may help protect the skin from numerous environmental aggressors.


      To read this article in full you will need to make a payment


        • Pourzand C.
        • Tyrrell R.M.
        Apoptosis, the role of oxidative stress and the example of solar UV radiation.
        Photochem Photobiol. 1999; 70: 380-390
        • Rittie L.
        • Fisher G.J.
        UV-light-induced signal cascades and skin aging.
        Ageing Res Rev. 2002; 1: 705-720
        • Bickers D.R.
        • Athar M.
        Oxidative stress in the pathogenesis of skin disease.
        J Invest Dermatol. 2006; 126: 2565-2575
        • Jaiswal A.K.
        Nrf2 signaling in coordinated activation of antioxidant gene expression.
        Free Radic Biol Med. 2004; 36: 1199-1207
        • Morita A.
        • Torii K.
        • Maeda A.
        • Yamaguchi Y.
        Molecular basis of tobacco smoke-induced premature skin aging.
        J Investig Dermatol Symp Proc. 2009; 14: 53-55
        • Ishii T.
        • Itoh K.
        • Yamamoto M.
        Roles of nrf2 in activation of antioxidant enzyme genes via antioxidant responsive elements.
        Methods Enzymol. 2002; 348: 182-190
        • Klaunig J.E.
        • Kamendulis L.M.
        • Hocevar B.A.
        Oxidative stress and oxidative damage in carcinogenesis.
        Toxicol Pathol. 2010; 38: 96-109
      1. Southall M.D. Kaur S. Mahmood K. The botanical extract feverfew pfe reduces DNA damage and induces DNA repair processes. InTech, San Diego2011
        • Itoh K.
        • Tong K.I.
        • Yamamoto M.
        Molecular mechanism activating nrf2-keap1 pathway in regulation of adaptive response to electrophiles.
        Free Radic Biol Med. 2004; 36: 1208-1213
        • Li W.
        • Kong A.N.
        Molecular mechanisms of Nrf2-mediated antioxidant response.
        Mol Carcinog. 2009; 48: 91-104
        • Kim S.G.
        • Lee S.J.
        PI3K, RSK, and MTOR signal networks for the gst gene regulation.
        Toxicol Sci. 2007; 96: 206-213
        • Itoh K.
        • Chiba T.
        • Takahashi S.
        • Ishii T.
        • Igarashi K.
        • Katoh Y.
        • et al.
        An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements.
        Biochem Biophys Res Commun. 1997; 236: 313-322
        • Kensler T.W.
        • Wakabayashi N.
        • Biswal S.
        Cell survival responses to environmental stresses via the keap1-Nrf2-are pathway.
        Annu Rev Pharmacol Toxicol. 2007; 47: 89-116
        • Na H.K.
        • Kim E.H.
        • Jung J.H.
        • Lee H.H.
        • Hyun J.W.
        • Surh Y.J.
        (-)-Epigallocatechin gallate induces Nrf2-mediated antioxidant enzyme expression via activation of PI3K and ERK in human mammary epithelial cells.
        Arch Biochem Biophys. 2008; 476: 171-177
        • Keum Y.S.
        • Yu S.
        • Chang P.P.
        • Yuan X.
        • Kim J.H.
        • Xu C.
        • et al.
        Mechanism of action of sulforaphane: inhibition of p38 mitogen-activated protein kinase isoforms contributing to the induction of antioxidant response element-mediated heme oxygenase-1 in human hepatoma hepg2 cells.
        Cancer Res. 2006; 66: 8804-8813
        • Lee J.S.
        • Surh Y.J.
        Nrf2 as a novel molecular target for chemoprevention.
        Cancer Lett. 2005; 224: 171-184
        • Kohen R.
        Skin antioxidants: their role in aging and in oxidative stress – new approaches for their evaluation.
        Biomed Pharmacother. 1999; 53: 181-192
        • Masella R.
        • Di Benedetto R.
        • Vari R.
        • Filesi C.
        • Giovannini C.
        Novel mechanisms of natural antioxidant compounds in biological systems: involvement of glutathione and glutathione-related enzymes.
        J Nutr Biochem. 2005; 16: 577-586
        • Johnson J.
        • Maher P.
        • Hanneken A.
        The flavonoid, eriodictyol, induces long-term protection in arpe-19 cells through its effects on Nrf2 activation and phase 2 gene expression.
        Invest Ophthalmol Vis Sci. 2009; 50: 2398-2406
        • Martin K.
        • Sur R.
        • Liebel F.
        • Tierney N.
        • Lyte P.
        • Garay M.
        • et al.
        Parthenolide-depleted feverfew (Tanacetum parthenium) protects skin from UV irradiation and external aggression.
        Arch Dermatol Res. 2008; 300: 69-80
        • Braun S.
        • Hanselmann C.
        • Gassmann M.G.
        • auf dem Keller U.
        • Born-Berclaz C.
        • Chan K.
        • et al.
        Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound.
        Mol Cell Biol. 2002; 22: 5492-5505
        • Leung L.
        • Kwong M.
        • Hou S.
        • Lee C.
        • Chan J.Y.
        Deficiency of the Nrf1 and Nrf2 transcription factors results in early embryonic lethality and severe oxidative stress.
        J Biol Chem. 2003; 278: 48021-48029
        • Schafer M.
        • Dutsch S.
        • auf dem Keller U.
        • Navid F.
        • Schwarz A.
        • Johnson D.A.
        • et al.
        Nrf2 establishes a glutathione-mediated gradient of UVB cytoprotection in the epidermis.
        Genes Dev. 2010; 24: 1045-1058
        • Kawachi Y.
        • Xu X.
        • Taguchi S.
        • Sakurai H.
        • Nakamura Y.
        • Ishii Y.
        • et al.
        Attenuation of UVB-induced sunburn reaction and oxidative DNA damage with no alterations in UVB-induced skin carcinogenesis in Nrf2 gene-deficient mice.
        J Invest Dermatol. 2008; 128: 1773-1779
        • Nguyen T.
        • Yang C.S.
        • Pickett C.B.
        The pathways and molecular mechanisms regulating Nrf2 activation in response to chemical stress.
        Free Radic Biol Med. 2004; 37: 433-441
        • Pi J.
        • Bai Y.
        • Reece J.M.
        • Williams J.
        • Liu D.
        • Freeman M.L.
        • et al.
        Molecular mechanism of human Nrf2 activation and degradation: role of sequential phosphorylation by protein kinase ck2.
        Free Radic Biol Med. 2007; 42: 1797-1806
        • Villeneuve N.F.
        • Sun Z.
        • Chen W.
        • Zhang D.D.
        Nrf2 and p21 regulate the fine balance between life and death by controlling ROS levels.
        Cell Cycle. 2009; 8: 3255-3256
        • Cantley L.C.
        The phosphoinositide 3-kinase pathway.
        Science. 2002; 296: 1655-1657
        • Lee Y.J.
        • Jeong H.Y.
        • Kim Y.B.
        • Won S.Y.
        • Shim J.H.
        • Cho M.K.
        • et al.
        Reactive oxygen species and PI3K/Akt signaling play key roles in the induction of Nrf2-driven heme oxygenase-1 expression in sulforaphane-treated human mesothelioma MSTO-211H cells.
        Food Chem Toxicol. 2012; 50: 116-1123
        • Dinkova-Kostova A.T.
        • Jenkins S.N.
        • Fahey J.W.
        • Ye L.
        • Wehage S.L.
        • Liby K.T.
        • et al.
        Protection against UV-light-induced skin carcinogenesis in skh-1 high-risk mice by sulforaphane-containing broccoli sprout extracts.
        Cancer Lett. 2006; 240: 243-252
        • Talalay P.
        • Fahey J.W.
        • Healy Z.R.
        • Wehage S.L.
        • Benedict A.L.
        • Min C.
        • et al.
        Sulforaphane mobilizes cellular defenses that protect skin against damage by uv radiation.
        Proc Natl Acad Sci USA. 2007; 104: 17500-17505
        • Katiyar S.K.
        • Afaq F.
        • Perez A.
        • Mukhtar H.
        Green tea polyphenol (-)-epigallocatechin-3-gallate treatment of human skin inhibits ultraviolet radiation-induced oxidative stress.
        Carcinogenesis. 2001; 22: 287-294
        • Zhao J.F.
        • Zhang Y.J.
        • Jin X.H.
        • Athar M.
        • Santella R.M.
        • Bickers D.R.
        • et al.
        Green tea protects against psoralen plus ultraviolet a-induced photochemical damage to skin.
        J Invest Dermatol. 1999; 113: 1070-1075
        • Natsch A.
        The Nrf2-keap1-are toxicity pathway as a cellular sensor for skin sensitizers – functional relevance and a hypothesis on innate reactions to skin sensitizers.
        Toxicol Sci. 2010; 113: 284-292
        • Ade N.
        • Leon F.
        • Pallardy M.
        • Peiffer J.L.
        • Kerdine-Romer S.
        • Tissier M.H.
        • et al.
        HMOX1 and NQO1 genes are upregulated in response to contact sensitizers in dendritic cells and thp-1 cell line: role of the keap1/Nrf2 pathway.
        Toxicol Sci. 2009; 107: 451-460
        • Natsch A.
        • Emter R.
        Skin sensitizers induce antioxidant response element dependent genes: application to the in vitro testing of the sensitization potential of chemicals.
        Toxicol Sci. 2008; 102: 110-119
        • Zhang Y.
        • Kensler T.W.
        • Cho C.G.
        • Posner G.H.
        • Talalay P.
        Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates.
        Proc Natl Acad Sci USA. 1994; 91: 3147-3150
        • Chen C.Y.
        • Jang J.H.
        • Li M.H.
        • Surh Y.J.
        Resveratrol upregulates heme oxygenase-1 expression via activation of Nf-E2-related factor 2 in PC12 cells.
        Biochem Biophys Res Commun. 2005; 331: 993-1000
        • Seo W.Y.
        • Goh A.R.
        • Ju S.M.
        • Song H.Y.
        • Kwon D.J.
        • Jun J.G.
        • et al.
        Celastrol induces expression of heme oxygenase-1 through ROS/Nrf2/are signaling in the hacat cells.
        Biochem Biophys Res Commun. 2011; 407: 535-540
        • Sauvaigo S.
        • Caillat S.
        • Odin F.
        • Nkengne A.
        • Bertin C.
        • Oddos T.
        Effect of aging on DNA excision/synthesis repair capacities of human skin fibroblasts.
        J Invest Dermatol. 2010; 130: 1739-1741
        • Pons B.
        • Belmont A.S.
        • Masson-Genteuil G.
        • Chapuis V.
        • Oddos T.
        • Sauvaigo S.
        Age-associated modifications of base excision repair activities in human skin fibroblast extracts.
        Mech Ageing Dev. 2010; 131: 661-665
        • Ben-Dor A.
        • Steiner M.
        • Gheber L.
        • Danilenko M.
        • Dubi N.
        • Linnewiel K.
        • et al.
        Carotenoids activate the antioxidant response element transcription system.
        Mol Cancer Ther. 2005; 4: 177-186
        • Maher P.
        • Hanneken A.
        Flavonoids protect retinal ganglion cells from oxidative stress-induced death.
        Invest Ophthalmol Vis Sci. 2005; 46: 4796-4803
        • Balogun E.
        • Hoque M.
        • Gong P.
        • Killeen E.
        • Green C.J.
        • Foresti R.
        • et al.
        Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element.
        Biochem J. 2003; 371: 887-895