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Two new adenopeptins B and C inhibit sphere formation of pancreatic cancer cells

The Journal of Antibiotics volume 77, pages 73–84 (2024)Cite this article

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Abstract

Cancer remains one of the leading causes of death worldwide, particularly pancreatic cancer being lethal because of its aggressiveness and lack of early detection methods. A factor that contributes to malignancy are cancer stem cell-like characteristics promoted by the tumor–stromal interaction. Given that fibroblast conditioned medium (CM) promotes sphere formation of cancer cells, a cancer stem cell-like characteristic, its inhibitor could be a new anticancer agent. By exploring microbial cultures as a source, we found new compounds, namely, adenopeptins B (1) and C (2), from Acremonium sp. ESF00140. 1 and 2 selectively and potently inhibited the sphere formation of pancreatic cancer cells cultured in the fibroblast CM compared with the control medium. Oxygen consumption rate (OCR) assays showed that 1 and 2 inhibit OCR in pancreatic cancer cells. Studies of similar compounds suggested mitochondrial complex V inhibition. Therefore, results of measuring the activity of human mitochondrial complex V revealed that 1 and 2 inhibited its activity. Oligomycin A, an inhibitor of mitochondrial complex V, as well as 1 and 2, strongly inhibited the sphere formation of pancreatic cancer cells cultured in fibroblast CM. The addition of 1 and 2 to pancreatic cancer cells cultured in fibroblast CM increased reactive oxygen species (ROS) production compared with that in the control medium. In pancreatic cancer cells cultured in fibroblast CM, mitochondria significantly influence sphere formation, and targeting their function with 1 and 2 might provide a new therapeutic approach for pancreatic cancer.

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Acknowledgements

We thank Ms. Yumiko Kubota, Dr. Shinya Adachi, and Dr. Kiyoko Iijima for the measurements of NMR and MS spectrum. We also thank Ms. Tamami Yoshida, Ms. Satomi Unno, and Ms. Rina Ando for their technical assistance. We thank the Support group for Molecular Profiling of Advanced Animal Model Support by a Grant-in-Aid for Scientific Research on Innovative Areas, Scientific Support Programs for Cancer Research, from The Ministry of Education, Culture, Sports, Science and Technology, Japan, for providing us with the SCADS inhibitor kits.

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Author notes

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

Authors and Affiliations

  1. Laboraroty of Oncology, Institute of Microbial Chemistry (BIKAKEN), Microbial Chemistry Research Foundation, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo, 141-0021, Japan

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

  2. Laboratory of Molecular Structure Analysis, Institute of Microbial Chemistry (BIKAKEN), Microbial Chemistry Research Foundation, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo, 141-0021, Japan

    Ryuichi Sawa

  3. Laboraroty of Microbiology, Institute of Microbial Chemistry (BIKAKEN), Microbial Chemistry Research Foundation, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo, 141-0021, Japan

    Hideyuki Muramatsu & Masayuki Igarashi

  4. Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, 18-24 Miyamoto, Numazu-shi, Shizuoka, 410-0301, Japan

    Tomokazu Ohishi

Authors
  1. Daisuke Tatsuda
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  9. Manabu Kawada
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Correspondence to Manabu Kawada.

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Tatsuda, D., Amemiya, M., Nosaka, C. et al. Two new adenopeptins B and C inhibit sphere formation of pancreatic cancer cells. J Antibiot 77, 73–84 (2024). https://doi.org/10.1038/s41429-023-00679-y

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