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New oligomycin derivatives inhibit anchorage-independent growth of pancreatic cancer cells

The Journal of Antibiotics volume 78, pages 436–441 (2025)Cite this article

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Abstract

Cancer stem cells (CSCs) play a crucial role in cancer progression, recurrence, and therapy resistance through their abilities to self-renew, differentiate, and evade treatment. Disrupting the interaction between CSCs and their tumor microenvironment, especially cancer-associated fibroblasts (CAFs), represents a promising therapeutic strategy. We screened microbial metabolites to identify compounds that specifically inhibit anchorage-independent (3D) growth, a key characteristic of CSCs, in the presence of CAF-conditioned medium (CAF-CM). Two new oligomycin analogs, oligomycins EX-1 (1) and 2 (2), were successfully isolated from Nocardia sp. MK165-SF8. Structural analysis using NMR and MS techniques revealed their distinctive chemical characteristics, particularly the presence of an exomethylene group. In biological assays, 1 and 2 demonstrated potent inhibitory activity against mitochondrial complex V, comparable to oligomycin A. Additionally, they showed enhanced effectiveness in suppressing both 3D growth and the expression of CD44 variants in pancreatic cancer cells cultured in CAF-CM.

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References

  1. Bahmad HF, Cheaito K, Chalhoub RM, Hadadeh O, Monzer A, Ballout F, et al. Sphere-formation assay: three-dimensional in vitro culturing of prostate cancer stem/progenitor sphere-forming cells. Front Oncol. 2018;8:347.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  3. Vlashi E, Pajonk F. Cancer stem cells, cancer cell plasticity and radiation therapy. Semin Cancer Biol. 2015;31:28–35.

    Article  CAS  PubMed  Google Scholar 

  4. Medema JP. Cancer stem cells: the challenges ahead. Nat Cell Biol. 2013;15:338–44.

    Article  CAS  PubMed  Google Scholar 

  5. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6:392–401.

    Article  CAS  PubMed  Google Scholar 

  6. Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16:582–98.

    Article  CAS  PubMed  Google Scholar 

  7. Maman S, Witz IP. A history of exploring cancer in context. Nat Rev Cancer. 2018;18:359–76.

    Article  CAS  PubMed  Google Scholar 

  8. Tatsuda D, Yoshida J, Ohishi T, Kawada M. Pancreatic stromal cell-derived oncostatin M confers drug resistance to a multi-tyrosine kinase inhibitor in pancreatic cancer cells. Anticancer Res. 2023;43:2477–89.

    Article  CAS  PubMed  Google Scholar 

  9. Zhao H, Yan C, Hu Y, Mu L, Huang K, Li Q, et al. Sphere‑forming assay vs. organoid culture: Determining long‑term stemness and the chemoresistant capacity of primary colorectal cancer cells. Int J Oncol. 2019;54:893–904.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Jubelin C, Munoz-Garcia J, Griscom L, Cochonneau D, Ollivier E, Heymann MF, et al. Three-dimensional in vitro culture models in oncology research. Cell Biosci. 2022;12:155.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Zhou B, Xu JW, Cheng YG, Gao JY, Hu SY, Wang L, et al. Early detection of pancreatic cancer: Where are we now and where are we going?. Int J Cancer. 2017;141:231–41.

    Article  CAS  PubMed  Google Scholar 

  12. Muggilli M, Russell D, Zhou Z. Comparison of programmed death ligand 1 immunostaining for pancreatic ductal adenocarcinoma between paired cytological and surgical samples. Cytojournal. 2021;18:28.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Tatsuda D, Amemiya M, Nosaka C, Sawa R, Muramatsu H, Igarashi M, et al. Two new adenopeptins B and C inhibit sphere formation of pancreatic cancer cells. J Antibiot. 2024;77:73–84.

    Article  CAS  Google Scholar 

  14. Enomoto Y, Shiomi K, Matsumoto A, Takahashi Y, Iwai Y, Harder A, et al. Isolation of a new antibiotic oligomycin G produced by Streptomyces sp. WK-6150. J Antibiot. 2001;54:308–13.

    Article  CAS  Google Scholar 

  15. Kono M, Kasai M, Shirahata K, Morimoto M. The derivation of 1a-demethylmitomycin G from mitomycin C. J Antibiot. 1990;43:383–90.

    Article  CAS  Google Scholar 

  16. Vaamonde-Garcia C, Loureiro J, Lopez-Pelaez E, Centeno-Cortes A, Riveiro-Naveira RR, Valcarcel-Ares MN, et al. Oligomycin, an inhibitor of complex V of the mitochondrial respiratory chain, induces an inflammatory and oxidative response in rat knee joint. Osteoarthr Cartil. 2014;22:S293–4.

    Article  Google Scholar 

  17. Luo Y, Tian Z, Hua X, Huang M, Xu J, Li J, et al. Isorhapontigenin (ISO) inhibits stem cell-like properties and invasion of bladder cancer cell by attenuating CD44 expression. Cell Mol Life Sci. 2020;77:351–63.

    Article  CAS  PubMed  Google Scholar 

  18. Ikeda H, Kawami M, Imoto M, Kakeya H. Identification of the polyether ionophore lenoremycin through a new screening strategy for targeting cancer stem cells. J Antibiot. 2022;75:671–8.

    Article  CAS  Google Scholar 

  19. Ishimoto T, Nagano O, Yae T, Tamada M, Motohara T, Oshima H, et al. CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and thereby promotes tumor growth. Cancer Cell. 2011;19:387–400.

    Article  CAS  PubMed  Google Scholar 

  20. Nagano O, Okazaki S, Saya H. Redox regulation in stem-like cancer cells by CD44 variant isoforms. Oncogene. 2013;32:5191–8.

    Article  CAS  PubMed  Google Scholar 

  21. Yan Y, Zuo X, Wei D. Concise review: emerging role of CD44 in cancer stem cells: a promising biomarker and therapeutic target. Stem Cells Transl Med. 2015;4:1033–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful to Dr. Shinya Adachi and Dr. Kiyoko Iijima for conducting the NMR and MS spectral analyses. We also thank Dr. Atsuko Matsumoto and Ms. Tamami Yoshida for performing the fermentation of MK165-SF8, Ms. Sayaka Jibiki for analyzing the 16S rDNA sequence of strain MK165-SF8, and Ms. Satomi Unno, Ms. Izuho Suwa, and Ms. Tomoko Miyazawa for their valuable technical support.

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Author notes

  1. These authors contributed equally: Daisuke Tatsuda, Masahide Amemiya

Authors and Affiliations

  1. Laboratory of Oncology, Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, Japan

    Daisuke Tatsuda, Masahide Amemiya, Chisato Nosaka, Junjiro Yoshida, Tomokazu Ohishi & Manabu Kawada

  2. Laboratory of Molecular Structure Analysis, Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, Japan

    Yumiko Kubota & Ryuichi Sawa

  3. Laboratory of Microbiology, Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, Japan

    Hideyuki Muramatsu & Masayuki Igarashi

  4. Institute of Microbial Chemistry (BIKAKEN), Numazu branch, Numazu-shi, Shizuoka, Japan

    Tomokazu Ohishi

Authors
  1. Daisuke Tatsuda
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  2. Masahide Amemiya
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  3. Chisato Nosaka
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  10. Manabu Kawada
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Correspondence to Manabu Kawada.

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Tatsuda, D., Amemiya, M., Nosaka, C. et al. New oligomycin derivatives inhibit anchorage-independent growth of pancreatic cancer cells. J Antibiot 78, 436–441 (2025). https://doi.org/10.1038/s41429-025-00832-9

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