Inhibition of DNA Polymerase λ Suppresses 12-O-Tetradecanoylphorbol- 13-Acetate-Induced Inflammation

We found that compounds, which can selectively inhibit the activity of mammalian DNA polymerase λ (pol λ) in vitro, show an anti-12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammatory effect in mice. Originally, we screened selective inhibitors for each of the mammalian DNA polymerases, and found two novel pol λ-inhibitors, phenolic compounds termed petasiphenol and curcumin (diferuloylmethane). Curcumin is known as an anti-chronic inflammatory agent and structurally quite similar to petasiphenol. The IC50 values of petasiphenol and curcumin for pol λ were 7.8 μM and 7.0 μM, respectively, and neither compound influenced any other mammalian DNA polymerases. Expectedly, petasiphenol also showed an anti-TPA-induced inflammatory effect. A relationship between the pol λ-inhibition and the anti-inflammatory activity is suggested. Therefore, we investigated whether other anti-inflammatory compounds such as terpeno benzoic acids, triterpene acids and epolactaene derivatives could be pol λ-inhibitors. Although all the compounds influenced not only several different DNA polymerase species but DNA topoisomerase II, they all most efficiently inhibited the pol λ-activity. These results unexpectedly suggest that there is a physiological relationship between pol l inhibition and anti-TPA-induced inflammation. This finding may provide insight into the molecular mechanism of TPAinduced inflammation, or neoplastic promotion.