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Analyses of the possible anti-tumor effect of yokukansan

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Abstract

The Kampo medicine yokukansan (YKS) has a wide variety of properties such as anxiolytic, anti-inflammatory and analgesic effects, and is also thought to regulate tumor suppression. In this study, we investigated the anti-tumor effect of YKS. We used Lewis lung carcinoma (LLC)-bearing mice that were fed food pellets containing YKS and then performed a fecal microbiota analysis, a microarray analysis for microRNAs (miRNAs) and an in vitro anti-tumor assay. The fecal microbiota analysis revealed that treatment with YKS partly reversed changes in the microbiota composition due to LLC implantation. Furthermore, a miRNA array analysis using blood serum showed that treatment with YKS restored the levels of miR-133a-3p/133b-3p, miR-1a-3p and miR-342-3p following LLC implantation to normal levels. A TargetScan analysis revealed that the epidermal growth factor receptor 1 signaling pathway is one of the major target pathways for these miRNAs. Furthermore, treatment with YKS restored the levels of miR-200b-3p and miR-200c-3p, a recognized mediator of cancer progression and controller of emotion, in the hypothalamus of mice bearing LLC. An in vitro assay revealed that a mixture of pachymic acid, saikosaponins a and d and isoliquiritigenin, which are all contained in YKS, exerted direct and additive anti-tumor effects. The present findings constitute novel evidence that YKS may exert an anti-tumor effect by reversing changes in the fecal microbiota and miRNAs circulating in the blood serum and hypothalamus, and the compounds found in YKS could have direct and additive anti-tumor effects.

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Abbreviations

CF:

Control food

CTLA-4:

Cytotoxic T lymphocyte-associated protein 4

EGFR:

Epidermal growth factor receptor

HPA:

Hypothalamic–pituitary–adrenal

IL-6:

Interleukin-6

LLC:

Lewis lung carcinoma

miRNAs:

MicroRNAs

N.Acc:

Nucleus accumbens

NSCLC:

Non-small cell lung cancer

NT:

Non-tumor

YKS:

Yokukansan

YKSF:

YKS-treated food

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Acknowledgements

We thank H. Kazamatsuri, M. Nakahama, W. Eguchi, and J.L. Waddington for their support. This work was supported by grants from MEXT (Ministry of Education, Culture, Sports, Science and Technology, Japan)-Supported Program for the Strategic Research Foundation at Private Universities, 2014–2018, S1411019.

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  1. Cheolsun Han and Miho Kawata contributed equally to this work.

Authors and Affiliations

  1. Department of Hospital Administration, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, 113-8421, Japan

    Cheolsun Han & Hiroyuki Kobayashi

  2. Center of Advanced Kampo Medicine and Clinical Research, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, 113-8421, Japan

    Cheolsun Han & Hiroyuki Kobayashi

  3. Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Science, Shinagawa-ku, Tokyo, 142-8501, Japan

    Cheolsun Han, Miho Kawata, Yusuke Hamada, Takashige Kondo, Junna Wada, Katsunori Asano, Hitoshi Makabe, Naoko Kuzumaki, Michiko Narita & Minoru Narita

  4. Department of Physiology, Fujita Health University, Toyoake, 470–1192, Japan

    Miho Kawata

  5. Life Science Tokyo Advanced Research Center (L-StaR), Hoshi University School of Pharmacy and Pharmaceutical Science, Shinagawa-ku, Tokyo, 142-8501, Japan

    Yusuke Hamada, Katsuhide Igarashi, Naoko Kuzumaki & Minoru Narita

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Contributions

Minoru N designed the research. CH, YH, TK, NK, KA, HM and Michiko N performed experiments. YH, TK, KA, HM and KI analyzed the data. HK, NK, Michiko N and Minoru N supervised the research. CH, MK and Minoru N wrote the paper.

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Correspondence to Cheolsun Han or Minoru Narita.

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Han, C., Kawata, M., Hamada, Y. et al. Analyses of the possible anti-tumor effect of yokukansan. J Nat Med 73, 468–479 (2019). https://doi.org/10.1007/s11418-019-01283-x

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