A parthenolide-depleted tanacetum parthenium extract induces DNA repair process through the PI3K-NRF2-ARE pathway

The NF-E2-related factor-2 (Nrf2) -antioxidant response element (ARE) pathway is one of the key cellular defense mechanisms that protect the cell from the effects of external aggressors by stimulating production of antioxidant and DNA repair genes. A Tanacetum parthenium (Feverfew) extract, which was depleted of parthenolide, induced nuclear translocation of Nrf2 and activated the ARE promoter in primary human keratinocytes. Blocking the de novo expression of Nrf2 by using specific siRNA diminished Feverfew-induced ARE promoter activity. Pre-treatment with LY294002, a selective pharmacological inhibitor of PI3 kinase led to a similar response suggesting that Feverfew activates the Nrf2-ARE pathway via PI3 kinase. In a comet assay, pretreatment with Feverfew enhanced the repair of DNA damage caused by UV in primary keratinocytes, and this effect was reversed by addition of the PI3 kinase inhibitor LY294002. Activation of DNA repair genes apurinic/apyrimidinic endonuclease-1 (APE-1) and DNA-damage binding protein-1 (DDB-1) by Feverfew was confirmed by western blot analysis of human skin equivalents topically treated with Feverfew. Through its ability to enhance endogenous antioxidant levels and induce DNA repair mechanisms in skin cells via activation of the Nrf2-ARE pathway, a purified Feverfew extract may protect skin from the harmful effects of numerous external aggressors, including UV radiation.