Chemopreventive effects and anti-tumorigenic mechanisms of Actinidia arguta, known as sarunashi in Japan toward 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)- induced lung tumorigenesis in a/J mouse

Jun Takata; Naoko Miyake; Yusuke Saiki; Misako Tada; Kensuke Sasaki; Toshio Kubo; Katsuyuki Kiura; Sakae Arimoto-Kobayashi

doi:10.1186/s41021-022-00255-0

Chemopreventive effects and anti-tumorigenic mechanisms of Actinidia arguta, known as sarunashi in Japan toward 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)- induced lung tumorigenesis in a/J mouse

Genes Environ. 2022 Dec 9;44(1):26. doi: 10.1186/s41021-022-00255-0.

Authors

Jun Takata¹, Naoko Miyake², Yusuke Saiki¹, Misako Tada², Kensuke Sasaki¹, Toshio Kubo³, Katsuyuki Kiura³, Sakae Arimoto-Kobayashi^{4

5}

Affiliations

¹ Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, 700-8530, Japan.
² Faculty of Pharmaceutical Sciences, Okayama University, Okayama, 700-8530, Japan.
³ Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, 700-8530, Japan.
⁴ Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, 700-8530, Japan. sakaearimoto@gmail.com.
⁵ Faculty of Pharmaceutical Sciences, Okayama University, Okayama, 700-8530, Japan. sakaearimoto@gmail.com.

Abstract

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 (ogt_ST and ada_ST) 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 ogt_ST and ada_ST. 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.

Keywords: Akt signal transduction; Anti-mutagenesis; DNA methylation; Isoquercetin; Lung tumorigenesis; Tobacco-specific nitrosamine.