RESUMEN
BACKGROUND: Previously, we reported the inhibitory effect of Actinidia arguta juice, known as sarunashi juice (sar-j) in Japan, on mutagenesis, inflammation, and mouse skin tumorigenesis. The components of A. arguta responsible for the anti-mutagenic effects were identified to be water-soluble, heat-labile phenolic compounds. We proposed isoquercetin (isoQ) as a candidate anticarcinogenic component. In this study, we sought to investigate the chemopreventive effects of A. arguta juice and isoQ on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice, and identify the possible mechanisms underlying the anti-tumorigenic effects of A. arguta. RESULTS: The number of tumor nodules per mouse lung in the group injected with NNK and administered A. arguta juice orally was significantly lower than that in the group injected with NNK only. Oral administration of isoQ also reduced the number of nodules in the mouse lungs. As expected, the mutagenicity of NNK and 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) detected using S. typhimurium TA1535 decreased in the presence of sar-j. However, NNK and MNNG mutagenicity detected using S. typhimurium YG7108, a strain lacking the O6-methylguanine DNA methyltransferases (ogtST and adaST) did not decrease in the presence of sar-j suggesting that sar-j may mediate its antimutagenic effect by enhancing the DNA damage repair by ogtST and adaST. Phosphorylation of Akt, with or without epidermal growth factor stimulation, in A549 cells was significantly decreased following sar-j and isoQ treatment, indicating that components in sar-j including isoQ suppressed the PI3K/AKT signaling pathways. CONCLUSIONS: Sar-j and isoQ reduced NNK-induced lung tumorigenesis. Sar-j targets both the initiation and growth/progression steps during carcinogenesis, specifically via anti-mutagenesis, stimulation of alkyl DNA adduct repair, and suppression of Akt-mediated growth signaling. IsoQ might contribute in part to the biological effects of sar-j via suppression of Akt phosphorylation, but it may not be the main active ingredient.
RESUMEN
BACKGROUND: Actinidia arguta, known as sarunashi in Japan, is a vine tree native to east-Asia, including Japan, that produces small fruit rich in anthocyanins, catechins, vitamin C, chlorophyll, beta-carotene and other polyphenols. RESULTS: Our study revealed the inhibitory effect of the juice of A. arguta (arguta-juice) toward the mutagenicity of food-derived carcinogens and polycyclic aromatic hydrocarbons using the Ames test, and antioxidant activity of arguta-juice as determined using a free radical scavenging assay. The formation of DNA adducts in liver of mice fed 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) decreased significantly following administration of arguta-juice. The preventive effect of arguta-juice on the induction of inflammation of mouse ear by 12-O-tetradecanoylphorbol-13-acetate (TPA) was revealed. The anti-carcinogenic effect of a topically applied partially purified fraction of A. arguta was revealed on skin tumorigenesis in mice induced by treatment with 7,12-dimethylbenz(a)anthracene and TPA. In an effort to reveal the mechanisms for antimutagenicity of arguta-juice, effects on the enzymes that metabolize xenobiotics were examined. Combined effects comprising i) inhibition of the metabolic activation of mutagens with phase I enzymes, but ii) no prevention on the activity of phase II detoxification enzyme, UGT, were observed. We also investigated the characterization and partial purification of the antimutagenic components in A. arguta, which suggested that the components in A. arguta responsible for the antimutagenicity were water-soluble, heat-labile phenolic compounds. CONCLUSIONS: These results suggested that components in A. arguta are attractive candidates for potential use as chemopreventive agents.
