No abstract

To determine whether fucoxanthin, a major carotenoid in brown sea algae, may activate cellular antioxidant enzymes via up-regulation of the Nrf2/antioxidant-response element (ARE) pathway, we incubated mouse hepatic BNL CL.2 cells with fucoxanthin (0.5-20 μM) for 0-24 h. We found that fucoxanthin (≥5 μM) significantly increased cellular reactive oxygen species (ROS) at 6 h of incubation, whereas preincubation with α-d-tocopherol (30 μM) significantly attenuated the increase of ROS, indicating the pro-oxidant nature of fucoxanthin. Fucoxanthin significantly increased the phosphorylation of ERK and p38 and markedly increased nuclear Nrf2 protein accumulation after incubation for 12 h. Moreover, fucoxanthin significantly enhanced binding activities of nuclear Nrf2 with ARE and increased mRNA and protein expression of HO-1 and NQO1 after incubation for 12 h. siRNA inhibition of Nrf2 led to markedly decreased HO-1 and NQO1 protein expression. Thus, fucoxanthin may exert its antioxidant activity, at least partly, through its pro-oxidant actions.

Cisplain, a platinum-containing anticancer drug, has been shown to enhance DNA repair and to inhibit cell apoptosis, leading to drug resistance. Thus, the combination of anticancer drugs with nutritional factors is a potential strategy for improving the efficacy of cisplatin chemotherapy. In this study, we investigated the anti-proliferative effects of a combination of fucoxanthin, the major non-provitamin A carotenoid found in Undaria Pinnatifida, and cisplatin in human hepatoma HepG2 cells. We found that fucoxanthin (1–10 μΜ) pretreatment for 24 h followed by cisplatin (10 μΜ) for 24 h significantly decreased cell proliferation, as compared with cisplatin treatment alone. Mechanistically, we showed that fucoxanthin attenuated cisplatin-induced NFκB expression and enhanced the NFκB-regulated Bax/Bcl-2 mRNA ratio. Cisplatin alone induced mRNA expression of excision repair cross complementation 1 (ERCC1) and thymidine phosphorylase (TP) through phosphorylation of ERK, p38 and PI3K/AKT pathways. However, fucoxanthin pretreatment significantly attenuated cisplatin-induced ERCC1 and TP mRNA expression, leading to improvement of chemotherapeutic efficacy of cisplatin. The results suggest that a combined treatment with fucoxanthin and cisplatin could lead to a potentially important new therapeutic strategy against human hepatoma cells.

Lycopene and its metabolite apo-10'-lycopenoic acid have been shown to induce phase II detoxifying/antioxidant enzymes through activation of the nuclear factor erythroid-derived 2-like 2 (Nrf2)-antioxidant response element (ARE) transcription system. However, little is known about whether apo-8'-lyocpenal, one of the main metabolites of lycopene in rat livers, in lycopene-containing food, and in human plasma, has similar effects. This study investigated the effect of apo-8'-lycopenal on Nrf2-ARE system-mediated heme oxygenase 1 (HO-1) and NAD(P)H:quinine oxidoreductase 1 (NQO-1) expression in human HepG2 cells. It was found that apo-8'-lycopenal (1-10 μM) significantly increased nuclear Nrf2 accumulation, ARE-luciferase activity, Nrf2-ARE binding activity, chymotrypsin-like activity, and downstream HO-1 and NQO-1 expression, but decreased cytosolic Kelch-like ECH-associated protein 1 (Keap1) expression. Results also revealed that the ERK/p38-Nrf2 pathway is involved in activation of HO-1 and NQO-1 expression by apo-8'-lycopenal using Nrf2 siRNA and ERK/p38 specific inhibitors. In addition, the activation time of lycopene on nuclear Nrf2 accumulation is slower than that of apo-8'-lycopenal, suggesting that the chemopreventive effects of lycopene may be partially attributed to its metabolites.

Pregnane X receptor (PXR) has been reported to regulate the expression of drug-metabolizing enzymes, such as the cytochrome P450 3A (CYP3A) family and transporters, such as multiple drug resistance 1 (MDR1). Fucoxanthin, the major carotenoid in brown sea algae, is a putative chemopreventive agent. In this study, we determined whether fucoxanthin could overcome drug resistance through attenuation of rifampin-induced CYP3A4 and MDR1 gene expression by PXR-mediated pathways in HepG2 hepatoma cells. We found that fucoxanthin (1–10 μM) significantly attenuated rifampin (20 μM)-induced CYP3A4, MDR1 mRNA and CYP3A4 protein expression at 24 h of incubation. Mechanistically, fucoxanthin strongly attenuated the PXR-mediated CYP3A4 promoter activity in HepG2 cells. In addition, fucoxanthin attenuated constitutive androstane receptor (CAR)- and rPXR-mediated CYP3A4 promoter activity in this cell line. Using the mammalian two-hybrid assay, we found that fucoxanthin significantly decreased the interaction between PXR and SRC-1, a PXR co-activator. Thus, fucoxanthin can decrease rifampin-induced CYP3A4 and MDR1 expression through attenuation of PXR-mediated CYP3A4 promoter activation and interaction between PXR and co-activator. These findings could lead to potentially important new therapeutic and dietary approaches to reduce the frequency of adverse drug reactions.