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Screening of growth inhibitors for epithelial–mesenchymal transition-induced cells by TGF-β from plant-based sources identified the active compound hydroxychavicol from Piper bitle

  • Natural Resource Letter
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Abstract

Epithelial–mesenchymal transition (EMT) has recently been associated with cancer invasion, metastasis, and resistance. In our previous study, we discovered nanaomycin K, a natural growth inhibitor for EMT-induced Madin Darby canine kidney (MDCK) cells, from the cultured broth of actinomycetes. However, the screening method was undeveloped, because the activity of nanaomycin K was discovered accidentally. In this study, we established a screening method by analyzing the characteristics of nanaomycin K in MDCK cells. Nanaomycin K showed the characteristic growth inhibitory activity on MDCK cells cultured under four conditions: medium containing dimethyl sulfoxide, SB431542, TGF-β, and a mixture of SB431542 and TGF-β. The activity was stronger in TGF-β-treated cells than in DMSO-treated cells. In the mixture of SB431542 and TGF-β-treated cells, the activity of nanaomycin K was suppressed. The anti-cancer agents, mitomycin C, cisplatin, and staurosporine, lacked the characteristics as that of nanaomycin K for these four treatment conditions. Since these four conditions distinguish between the effects of nanaomycin K and other anti-cancer agents in EMT-induced cells, the screening method was established. Among the 13,427 plant extracts tested, Piper betle leaf extract displayed growth inhibitory activity against EMT-induced cells. Through the purification of the extract via bio-guided fractionation, hydroxychavicol was isolated as an active compound. The cytotoxic activity of hydroxychavicol was stronger in EMT-induced MDCK cells than in control cells. However, its cytotoxic activity was suppressed in EMT-inhibited cells. Furthermore, hydroxychavicol exhibited same activity against SAS cells (human squamous cell carcinoma of the tongue). Thus, we have successfully established a screening method for growth inhibitors of EMT-induced cells and have discovered an inhibitor from plant-based sources.

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Acknowledgements

We thank Dr. Masato Iwatsuki and Distinguished Emeritus Professor Satoshi Ōmura (Kitasato University) for providing nanaomycin E.

Funding

This study was supported by a JSPS KAKENHI Grant (Grant Number: 21K06625) to H. Matsuo.

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Authors and Affiliations

  1. Tsukuba Division of Research Center for Medicinal Plant Resources, National Institutes of Biomedical Innovation, Health and Nutrition, 1-2 Hachimandai, Tsukuba, 305-8043, Japan

    Hirotaka Matsuo, Hitomi Kawakami, Noriaki Kawano, Hiroyuki Fuchino, Nobuo Kawahara & Kayo Yoshimatsu

  2. Tanegasima Division of Research Center for Medicinal Plant Resources, National Institutes of Biomedical Innovation, Health and Nutrition, 17007-2 Noma, Nakatane-cho, Kumage-gun, Kagoshima, 891-3604, Japan

    Naoko Anjiki

  3. The Kochi Prefectural Makino Botanical Garden, 4200-6 Godaisan, Kochi, 781-8125, Japan

    Nobuo Kawahara

Authors
  1. Hirotaka Matsuo
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  2. Hitomi Kawakami
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  3. Naoko Anjiki
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  4. Noriaki Kawano
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  5. Hiroyuki Fuchino
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  6. Nobuo Kawahara
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  7. Kayo Yoshimatsu
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Contributions

H. M. performed the screening, isolation, biological assay and described manuscript. H. K. prepared the plant extracts for screening. N. A. collected the Piper bitle. N. K. (Noriaki Kawano), H. F., N. K. (Nobuo Kawahara), and K. Y. supervised this study. All members were engaged in the collection of natural plant resources.

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Correspondence to Hirotaka Matsuo.

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Matsuo, H., Kawakami, H., Anjiki, N. et al. Screening of growth inhibitors for epithelial–mesenchymal transition-induced cells by TGF-β from plant-based sources identified the active compound hydroxychavicol from Piper bitle. J Nat Med (2024). https://doi.org/10.1007/s11418-024-01785-3

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  • DOI: https://doi.org/10.1007/s11418-024-01785-3

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