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A pipecolic acid-rich branched cyclic depsipeptide ulleungamide C from a Streptomyces species induces G0/G1 cell cycle arrest in promyelocytic leukemia cells

The Journal of Antibiotics volume 74, pages 181–189 (2021)Cite this article

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Abstract

In this study, screening by LC–MS and cytotoxicity-guided isolation led to the identification of ulleungamide C (1), a previously unknown pipecolic acid-rich branched cyclic depsipeptide, from a soil actinobacterium Streptomyces sp. KCB13F003. The structure of 1 was determined by interpretation of spectroscopic and spectrometric data from 1D and 2D NMR and HRESIMS experiments. Antiproliferative assays using mammalian cancerous cells revealed that 1 inhibits the proliferation of HL-60 human promyelocytic leukemia cells. Cell cycle analysis showed an increased accumulation of cells in the G0/G1 phase after treatment with 1. Results of immunoblotting assays revealed that 1 reduced the expression levels of cyclin-dependent kinase 4 (CDK4), CDK6, retinoblastoma protein (Rb), and phosphorylated Rb, whereas it induced cyclin-dependent kinase inhibitor 1B (p27/Kip1) expression.

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Acknowledgements

We thank Harumi Aono, Kai Yamamoto, Dr. Junnosuke Otaka, and Dr. Yushi Futamura in RIKEN Center for Sustainable Research Science for preliminary bioactivity tests. We also thank Dr. Shunji Takahashi in RIKEN for his helpful discussion about the ulleungamide family. This work was supported by the KRIBB Research Initiative Program and the R&D Convergence Program (CAP-16-03-KRIBB) of the National Research Council of Science and Technology (NST) funded by the Ministry of Science ICT (MIST) of the Republic of Korea. We thank the KBSI, Ochang, Korea, for providing the NMR and HRESIMS data.

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  1. Sangkeun Son

    Present address: Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, 02115, MA, USA

  2. These authors contributed equally: Sangkeun Son, Mina Jang

Authors and Affiliations

  1. Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, 28116, Republic of Korea

    Sangkeun Son, Mina Jang, Byeongsan Lee, Jun-Pil Jang, Young-Soo Hong, Bo Yeon Kim & Jong Seog Ahn

  2. Department of Biomolecular Science, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, 34113, Republic of Korea

    Young-Soo Hong, Bo Yeon Kim, Jae-Hyuk Jang & Jong Seog Ahn

  3. Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, 28116, Republic of Korea

    Sung-Kyun Ko & Jae-Hyuk Jang

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  1. Sangkeun Son
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Son, S., Jang, M., Lee, B. et al. A pipecolic acid-rich branched cyclic depsipeptide ulleungamide C from a Streptomyces species induces G0/G1 cell cycle arrest in promyelocytic leukemia cells. J Antibiot 74, 181–189 (2021). https://doi.org/10.1038/s41429-020-00385-z

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