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22-O-(N-Boc-l-glycine) ester of renieramycin M inhibits migratory activity and suppresses epithelial–mesenchymal transition in human lung cancer cells

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Abstract

The incidence of metastasis stage crucially contributes to high recurrence and mortality rate in lung cancer patients. Unfortunately, no available treatment inhibits migration, a key metastasis process in lung cancer. In this study, the effect of 22-O-(N-Boc-l-glycine) ester of renieramycin M (22-Boc-Gly-RM), a semi-synthetic amino ester derivative of bistetrahydroisoquinolinequinone alkaloid isolated from Xestospongia sp., on migratory behavior of human lung cancer cells was investigated. Following 24 h of treatment, 22-Boc-Gly-RM at non-toxic concentrations (0.5–1 μM) effectively restrained motility of human lung cancer H460 cells assessed through wound healing, transwell migration, and multicellular spheroid models. The capability to invade through matrix component was also repressed in H460 cells cultured with 0.1–1 µM 22-Boc-Gly-RM. The dose-dependent reduction of phalloidin-stained actin stress fibers corresponded with the downregulated Rac1-GTP level presented via western blot analysis in 22-Boc-Gly-RM-treated cells. Treatment with 0.1–1 μM of 22-Boc-Gly-RM obviously caused suppression of p-FAK/p-Akt signal and consequent inhibition of epithelial-to-mesenchymal transition (EMT), which was evidenced with augmented level of E-cadherin and reduction of N-cadherin expression. The alteration of invasion-related proteins in 22-Boc-Gly-RM-treated H460 cells was indicated by the diminution of matrix metalloproteinases (MT1-MMP, MMP-2, MMP-7, and MMP-9), as well as the upregulation of tissue inhibitors of metalloproteinases (TIMP), TIMP2, and TIMP3. Thus, 22-Boc-Gly-RM is a promising candidate for anti-metastasis treatment in lung cancer through inhibition of migratory features associated with suppression on EMT.

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Supplementary information 1: Semi-synthesis and spectroscopic data of 22-O-(N-Boc-l-glycine) ester of renieramycin M is available at Online Resource 1.

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Acknowledgements

The authors would like to thank the Natural Products and Nanoparticles Research Unit, NP2 (GRU 6306433004-1) and Cell-based Drug and Health Products Development Research Unit (GRU 6000833002-1) for collaboration and research facilities. Y.O. would like to thank Chulalongkorn University for the provision of the Scholarship for International Graduate Students in ASEAN Countries.

Funding

This research was supported by the 90th Anniversary of Chulalongkorn University and Ratchadaphiseksomphot Endowment Fund (Grant no. CU_GR_62_20_33_01) from Chulalongkorn University. Preparation of 22-O-(N-Boc-l-glycine) ester of renieramycin M was supported by the Mid-Career Research Grant, National Research Council of Thailand (NRCT), Thailand (RSA 6280009) to S.C.

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YO performed the experiments and prepared manuscript. JQLN interpreted the results and prepared manuscript. KS extracted the compound. SC extracted and semi-synthesized the compound, and prepared manuscript. GAUE interpreted the results of cancer spheroid-based migration and invasion assays and prepared manuscript. VP interpreted the results. PC interpreted the results. CC made substantial contributions to conception and experimental design, interpreted the results, and prepared manuscript.

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Correspondence to Chatchai Chaotham.

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Oo, Y., Nealiga, J.Q.L., Suwanborirux, K. et al. 22-O-(N-Boc-l-glycine) ester of renieramycin M inhibits migratory activity and suppresses epithelial–mesenchymal transition in human lung cancer cells. J Nat Med 75, 949–966 (2021). https://doi.org/10.1007/s11418-021-01549-3

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