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Identification of the polyether ionophore lenoremycin through a new screening strategy for targeting cancer stem cells

Abstract

Targeting and eradicating cancer stem cells (CSCs), also termed tumor-initiating cells, are promising strategies for preventing cancer progression and recurrence. To identify candidate compounds targeting CSCs, we established a new screening strategy with colorectal CSC spheres and non-CSC spheres in three-dimensional (3D) culture system. Through chemical screening using our system with in-house microbial metabolite library, we identified polyether cation ionophores that selectively inhibited CSC sphere formation, whereas CSC spheres were resistant to conventional anticancer agents. One of the hit compounds, the most selective and effective microbial metabolite lenoremycin, decreased CSC populations via inducing reactive oxygen species production. This study demonstrated that our newly established screening system is useful for discovering agents that selectively eliminate CSCs.

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Acknowledgements

We thank Shionogi & Co. Ltd for providing the three ionophores (lenoremycin sodium salt, nonactin, and nigericin sodium salt). This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (17H06401 (HK and MI), 19H02840 (HK), 22H04901 (HK)), and the Platform Project for Supporting Drug Discovery and Life Science Research from the Japan Agency for Medical Research and Development (AMED), Japan (HK).

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Correspondence to Hideaki Kakeya.

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Ikeda, H., Kawami, M., Imoto, M. et al. Identification of the polyether ionophore lenoremycin through a new screening strategy for targeting cancer stem cells. J Antibiot 75, 671–678 (2022). https://doi.org/10.1038/s41429-022-00571-1

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  • DOI: https://doi.org/10.1038/s41429-022-00571-1

Keywords

  • Cancer stem cells
  • Screening
  • Polyether ionophore
  • Reactive oxygen species

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