Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

The Journal of Antibiotics volume 75, pages 671–678 (2022)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5:275–84.

    Article  CAS  PubMed  Google Scholar 

  2. Batlle E, Clevers H. Cancer stem cells revisited. Nat Med. 2017;23:1124–34.

    Article  CAS  PubMed  Google Scholar 

  3. Saygin C, Matei D, Majeti R, Reizes O, Lathia JD. Targeting cancer stemness in the clinic: from hype to hope. Cell Stem Cell. 2019;24:25–40.

    Article  CAS  PubMed  Google Scholar 

  4. Takebe N, et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol. 2015;12:445–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yang L, et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther. 2020;5:1–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Jang MK, Mashima T, Seimiya H. Tankyrase inhibitors target colorectal cancer stem cells via AXIN-dependent downregulation of c-KIT tyrosine kinase. Mol Cancer Ther. 2020;19:765–76.

    Article  CAS  PubMed  Google Scholar 

  7. Sun HR, et al. Therapeutic strategies targeting cancer stem cells and their microenvironment. Front Oncol. 2019;9:1–14.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Madoux F, et al. A 1536-well 3D viability assay to assess the cytotoxic effect of drugs on spheroids. SLAS Discov. 2017;22:516–24.

    Article  CAS  PubMed  Google Scholar 

  9. Lal-Nag M, et al. A high-throughput screening model of the tumor microenvironment for ovarian cancer cell growth. SLAS Discov. 2017;22:494–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yan X, et al. High throughput scaffold-based 3D micro-tumor array for efficient drug screening and chemosensitivity testing. Biomaterials. 2019;198:167–79.

    Article  CAS  PubMed  Google Scholar 

  11. Gupta PB, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138:645–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kakeya H. Natural products-prompted chemical biology: phenotypic screening and a new platform for target identification. Nat Prod Rep. 2016;33:648–54.

    Article  CAS  PubMed  Google Scholar 

  13. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.

    Article  CAS  PubMed  Google Scholar 

  14. Munro MJ, Wickremesekera SK, Peng L, Tan ST, Itinteang T. Cancer stem cells in colorectal cancer: a review. J Clin Pathol. 2018;71:110–6.

    Article  CAS  PubMed  Google Scholar 

  15. Takeda K, et al. Sox2 is associated with cancer stem-like properties in colorectal cancer. Sci Rep. 2018;8:17639.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Najafi M, Farhood B, Mortezaee K. Cancer stem cells (CSCs) in cancer progression and therapy. J Cell Physiol. 2019;234:8381–95.

    Article  CAS  PubMed  Google Scholar 

  17. Deka J, et al. Bcl9/Bcl9l are critical for Wnt-mediated regulation of stem cell traits in colon epithelium and adenocarcinomas. Cancer Res. 2010;70:6619–28.

    Article  CAS  PubMed  Google Scholar 

  18. Lv J, et al. Cell softness regulates tumorigenicity and stemness of cancer cells. EMBO J. 2020;40:e106123.

    PubMed  PubMed Central  Google Scholar 

  19. Kubota T, Hinoh G, Mayama M, Motokawa K, Yasuda Y. Antibiotic A-130, isolation and characterization. J Antibiot. 1975;28:931–4.

    Article  CAS  Google Scholar 

  20. Westley JW. Polyether antibiotics: versatile carboxylic acid ionophores produced by Streptomyces. Adv Appl Microbiol. 1977;22:177–223.

    Article  CAS  PubMed  Google Scholar 

  21. Corbaz VR, et al. Nonactin. Helv Chim Acta. 1955;174:1445–8.

    Article  Google Scholar 

  22. Marrone TJ, Merz KM. Molecular recognition of potassium ion by the naturally occurring antibiotic ionophore nonactin. J Am Chem Soc. 1992;114:7542–9.

    Article  CAS  Google Scholar 

  23. Harned RL, Hidy PH, Corum CJ, Jones KL. Nigericin a new crystalline antibiotic from an unidentified Streptomyces. Antibiot Chemother. 1951;1:594–6.

    CAS  Google Scholar 

  24. Steinrauf LK, Pinkerton M, Chamberlin JW. The structure of nigericin. Biochem Biophys Res Commun. 1968;33:29–31.

    Article  CAS  PubMed  Google Scholar 

  25. Deng CC, et al. Nigericin selectively targets cancer stem cells in nasopharyngeal carcinoma. Int J Biochem Cell Biol. 2013;45:1997–2006.

    Article  CAS  PubMed  Google Scholar 

  26. Huang M, et al. Aglycone polyether nanchangmycin and its homologues exhibit apoptotic and antiproliferative activities against cancer stem cells. ACS Pharmacol Transl Sci. 2018;1:84–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lu D, et al. Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells. Proc Natl Acad Sci USA. 2011;108:13253–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ikeda H, et al. Miclxin, a Novel MIC60 inhibitor, induces apoptosis via mitochondrial stress in β-catenin mutant tumor cells. ACS Chem Biol. 2020;15:2195–204.

    Article  CAS  PubMed  Google Scholar 

  29. Kim KY, et al. Salinomycin-induced apoptosis of human prostate cancer cells due to accumulated reactive oxygen species and mitochondrial membrane depolarization. Biochem Biophys Res Commun. 2011;413:80–86.

    Article  CAS  PubMed  Google Scholar 

  30. Menke-van der Houven van Oordt CW, et al. First-in-human phase I clinical trial of RG7356, an anti-CD44 humanized antibody, in patients with advanced, CD44-expressing solid tumors. Oncotarget. 2016;7:80046–58.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Burges A, et al. Effective relief of malignant ascites in patients with advanced ovarian cancer by a trifunctional anti-EpCAM x anti-CD3 antibody: a phase I/II study. Clin Cancer Res. 2007;13:3899–905.

    Article  CAS  PubMed  Google Scholar 

  32. Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Discov. 2014;13:513–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rimkus TK, Carpenter RL, Qasem S, Chan M, Lo HW. Targeting the sonic hedgehog signaling pathway: review of smoothened and GLI inhibitors. Cancers. 2016;8:1–23.

    Article  Google Scholar 

  34. Andersson ER, Lendahl U. Therapeutic modulation of Notch signalling-are we there yet? Nat Rev Drug Discov. 2014;13:357–78.

    Article  CAS  PubMed  Google Scholar 

  35. Stock K, et al. Capturing tumor complexity in vitro: comparative analysis of 2D and 3D tumor models for drug discovery. Sci Rep. 2016;6:28951.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang H, et al. Anticancer mechanisms of salinomycin in breast cancer and its clinical applications. Front Oncol. 2021;11:654428.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Qi D, et al. Salinomycin as a potent anticancer stem cell agent: state of the art and future directions. Med Res Rev. 2022;42:1037–63.

    Article  CAS  PubMed  Google Scholar 

  38. Pádua D, et al. A SOX2 reporter system identifies gastric cancer stem-like cells sensitive to monensin. Cancers. 2020;12:495.

    Article  PubMed Central  Google Scholar 

  39. Tamai Y, et al. Nonactin and related compounds found in a screening program for Wnt signal inhibitory activity. Heterocylces. 2012;84:1245–50.

    Article  CAS  Google Scholar 

  40. Shikata Y, et al. Mitochondrial uncoupler exerts a synthetic lethal effect against β-catenin mutant tumor cells. Cancer Sci. 2017;108:772–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

  1. Department of System Chemotherapy and Molecular Sciences, Division of Medicinal Frontier Sciences, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan

    Hiroaki Ikeda, Misato Kawami & Hideaki Kakeya

  2. Department of Neurology, Division for Development of Autophagy Modulating Drugs, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan

    Masaya Imoto

Authors
  1. Hiroaki Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Misato Kawami
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masaya Imoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hideaki Kakeya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hideaki Kakeya.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

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

Keywords

This article is cited by

Search

Advanced search

Quick links