Isoalantolactone fromInula heleniumCaused Nrf2-Mediated Induction of Detoxifying Enzymes

Abstract

Our previous study demonstrated that methanolic extract of Inula helenium (Elecampane) has the potential to induce detoxifying enzymes such as NAD(P)H:(quinone acceptor) oxidoreductase 1 (EC 1.6.99.2) (NQO1, QR) activity and glutathione S-transferase (GST) and found isoalantolactone and alantolactone as the active components. In this study we investigated the detoxifying enzyme-inducing potential of isoalantolactone, which is present in I. helenium and has a structure similar to that of alantolactone. The compound induced QR in a dose-dependent manner in both Hepa1c1c7 cells and its mutant BPRc1 cells lacking the arylhydrocarbon receptor translocator. Like with most phase 2 enzyme inducers, other phase 2 detoxifying enzymes, including GST, glutathione reductase, gamma-glutamylcysteine synthetase, and heme oxygenase-1, were also induced by isoalantolactone in a dose-dependent manner in the cultured cells. Furthermore, isoalantolactone caused a proportionate increase in luciferase activity depending upon concentration and exposure time in the reporter assay in which HepG2-C8 cells, transfectants carrying antioxidant response element-luciferase gene, were used. The nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) was stimulated by the compound and attenuated by phosphatidylinositol 3-kinase inhibitors such as LY294002 and wortmannin. In conclusion, isoalantolactone is a candidate for chemoprevention and acts as potent phase 2 enzyme inducer by stimulating the accumulation of Nrf2 in the nucleus.

Alantolactone suppresses inducible nitric oxide synthase and cyclooxygenase-2 expression by down-regulating NF-κB, MAPK and AP-1 via the MyD88 signaling pathway in LPS-activated RAW 264.7 cells

“…For example, sesquiterpene lactones, such as parthenolide [11], helenalin [12] and costunolide [13], have been discovered to have potent inhibitory activities on NO production and NF-κB activation via downregulating the expression of iNOS and COX-2. Alantolactone, a sesquiterpene lactone, has been reported to have anti-proliferative [14] and detoxifying effects [15]. It was previously reported that alantolactone also exhibits an inhibitory effect on the production of NO [16].…”

Antioxidant activities of licorice-derived prenylflavonoids

“…Dehydroglyasperin C (DGC) and dehydroglyasperin D (DGD) in licorice are characterized by increased PPAR-gamma ligand-binding as well as anti-inflammatory activities [6,9], whereas isoangustone A (Iso A), another bioactive constituent, displays anti-bacterial [10] and anti-inflammatory activities in renal mesangial cells [11], along with apoptotic effects in prostate cancer cells [12,13]. It has also been reported that DGC plays an important role in cancer prevention by inducing detoxifying enzymes via activation of Nrf2/ARE [14]. Despite ample evidence that the ability of phytochemicals to induce the Nrf2 signaling pathway is closely related to their antioxidant activities in most cases, there is only limited information on the antioxidant activities of phenylflavonoids such as DGC in licorice.…”

Targeting Apoptosis Pathways in Cancer and Perspectives with Natural Compounds from Mother Nature

“…Oridonin activates Nrf2 signaling pathway, leading to accumulation of the Nrf2 protein and activation of the Nrf2-dependent cytoprotective response (87). Isoalantolactone stimulates the accumulation of Nrf2 in the nucleus of both Hepa1c1c7 cells and its mutant BPRc1 cells (88). Alantolactone also stimulated the nuclear accumulation of Nrf2 in HepG2-C8 cells (89).…”