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Analyses of the possible anti-tumor effect of yokukansan

  • Cheolsun HanEmail author
  • Miho Kawata
  • Yusuke Hamada
  • Takashige Kondo
  • Junna Wada
  • Katsunori Asano
  • Hitoshi Makabe
  • Katsuhide Igarashi
  • Naoko Kuzumaki
  • Michiko Narita
  • Hiroyuki Kobayashi
  • Minoru NaritaEmail author
Original Paper

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.

Keywords

Yokukansan Tumor MicroRNA Microbiota Hypothalamus 

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

Notes

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.

Author 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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© The Japanese Society of Pharmacognosy 2019

Authors and Affiliations

  • Cheolsun Han
    • 1
    • 2
    • 3
    Email author
  • Miho Kawata
    • 3
    • 4
  • Yusuke Hamada
    • 3
    • 5
  • Takashige Kondo
    • 3
  • Junna Wada
    • 3
  • Katsunori Asano
    • 3
  • Hitoshi Makabe
    • 3
  • Katsuhide Igarashi
    • 5
  • Naoko Kuzumaki
    • 3
    • 5
  • Michiko Narita
    • 3
  • Hiroyuki Kobayashi
    • 1
    • 2
  • Minoru Narita
    • 3
    • 5
    Email author
  1. 1.Department of Hospital AdministrationJuntendo University School of MedicineTokyoJapan
  2. 2.Center of Advanced Kampo Medicine and Clinical ResearchJuntendo University School of MedicineTokyoJapan
  3. 3.Department of PharmacologyHoshi University School of Pharmacy and Pharmaceutical ScienceTokyoJapan
  4. 4.Department of PhysiologyFujita Health UniversityToyoakeJapan
  5. 5.Life Science Tokyo Advanced Research Center (L-StaR)Hoshi University School of Pharmacy and Pharmaceutical ScienceTokyoJapan

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