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Cinnamon bark extract suppresses metastatic dissemination of cancer cells through inhibition of glycolytic metabolism

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Abstract

Metastasis is responsible for approximately 90% of cancer-associated mortality and proceeds through multiple steps. Several herbal medicines are reported to inhibit primary tumor growth, but the suppressor effects of the medicines on metastasis progression are still not fully elucidated. Here we report that cinnamon bark extract (CBE) has a suppressor effect on metastatic dissemination of cancer cells. Through a phenotypic screening using zebrafish embryos, CBE was identified to interfere with the gastrulation progression of zebrafish embryos, of which the molecular mechanisms are conserved in metastasis progression. A Boyden chamber assay showed that CBE decreased cell motility and invasion of MDA-MB-231 human breast cancer cells without affecting their cell viability. Furthermore, CBE suppressed metastatic dissemination of the cells in a zebrafish xenotransplantation model. Quantitative metabolome analyses revealed that the productions of glucose-6-phosphate (G6P) and fructose 6-phosphate which are intermediate metabolites of glycolytic metabolism were interrupted in CBE-treated cells. qPCR and western-blotting analyses revealed that CBE-treated cells showed decreased expression of hexokinase 2 (HK2) which yields G6P. Pharmacological inhibition of HK2 with 2-deoxy-D-glucose suppressed cell invasion and migration of the cells without affecting their cell viability. Taken together, CBE suppresses metastatic dissemination of cancer cells through inhibition of glycolysis metabolism.

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Acknowledgements

We sincerely appreciate Prof. Hayakawa (Institute of natural medicine, University of Toyama) and Dr. Shimada (Mie University) for providing the herbal medicine library and teaching methods of zebrafish xenotransplantation to us. All statistical analyses were consulted with Dr. Ohtsuki (Japan Institute of Statistical Technology). This research was performed as a part of the Cooperative Research Project with Institute of Natural Medicine, University of Toyama in 2021.

Funding

This work was supported in part by research funds from the Yamagata prefectural government and the City of Tsuruoka.

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Authors and Affiliations

  1. Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan

    Joji Nakayama, Ami Maruyama & Hideki Makinoshima

  2. Shonai Regional Industry Promotion Center, Tsuruoka, Japan

    Joji Nakayama, Ami Maruyama & Hideki Makinoshima

  3. Tsuruoka Minami High School, Tsuruoka, Japan

    Yuki Konno

  4. Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan

    Yuki Konno & Masaru Tomita

  5. Division of Translational Genomics, Exploratory Oncology Research and Clinical Trials Center, National Cancer Center, Kashiwa, Japan

    Hideki Makinoshima

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  1. Joji Nakayama
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  2. Yuki Konno
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  3. Ami Maruyama
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  4. Masaru Tomita
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  5. Hideki Makinoshima
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Contributions

Design research: J.N. Conducting experiments: J.N, Y.K. and A.M. Analyzing data: J.N., Y.K. and A.M. Writing the paper: J.N. Funding acquisition: M.T. and H.M. Supervision: J.N. and H.M.

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Correspondence to Joji Nakayama.

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J.N., Y.K.., A.M., M.T., and H.M. declare no conflict of interest.

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Nakayama, J., Konno, Y., Maruyama, A. et al. Cinnamon bark extract suppresses metastatic dissemination of cancer cells through inhibition of glycolytic metabolism. J Nat Med 76, 686–692 (2022). https://doi.org/10.1007/s11418-022-01624-3

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  • DOI: https://doi.org/10.1007/s11418-022-01624-3

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