Isoalantolactone from Inula helenium Caused Nrf2-Mediated Induction of Detoxifying Enzymes

Chemoprevention has been defined as the use of pharmacologic or natural agents designed to prevent, suppress, or reverse the process of carcinogenesis before the development of malignancy. One of the major mechanisms of chemical protection against carcinogenesis is the induction of phase 2 enzymes involved in detoxification of exogenous and endogenous mutagens and carcinogens. Antioxidant response element (ARE) is present in the promoter region of genes encoding for phase 2 detoxification=antioxidant enzymes such as heme oxygenase-1 (HO-1), NAD(P)H:(quinone acceptor) oxidoreductase 1 (EC 1.6.99.2) (NQO1, QR), and glutathione S-transferase (GST). In unstressed states, nuclear factor-E2-related factor 2 (Nrf2) is present in the cytoplasm in association with Kelch-like ECH-associated protein 1 (Keap1). Disturbance of the interaction between Nrf2 and Keap1, including covalent or oxidative modification of cysteine thiols in Keap1 by electrophiles or oxidative stress, results in Nrf2 release and its translocation into the nucleus. Binding of Nrf2 to the ARE sequence in genes encoding phase 2=antioxidant enzymes causes transcriptional activation of the relevant genes, promoting removal of reactive oxygen species or toxic chemicals. Many natural compounds such as curcumin, caffeic acid phenethyl ester, and sulforaphane are known to act as electrophiles in Nrf2= ARE activation.

Our previous study demonstrated that sesquiterpenes isolated from Inula helenium (also known as Elecampane) induced NQO1 (QR), an anticarcinogenic marker enzyme. In an attempt to elucidate the underlying mechanism of phase 2 enzyme induction by the sesquiterpene isoalantolactone, the effect of isoalantolactone (Fig. 1) on Nrf2=ARE activation was investigated.