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Nafamostat mesilate negatively regulates the metastasis of triple-negative breast cancer cells

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Abstract

Triple-negative breast cancer (TNBC) lacking of oestrogen receptor, progesterone receptor, and epidermal growth factor receptor type 2 is a highly malignant disease which results in a poor prognosis and rare treatment options. Despite the use of conventional chemotherapy for TNBC tumours, resistance and short duration responses limit the treatment efficacy. Therefore, a need exists to develop a new chemotherapy for TNBC. The aim of this study was to examine the anti-cancer effects of nafamostat mesilate (NM), a previously known serine protease inhibitor and highly safe drug on breast cancer cells. Here, we showed that NM significantly inhibits proliferation, migration, and invasion in MDA-MB231 cells, induces G2/M phase cell-cycle arrest, and inhibits the expression of cyclin-dependent kinase 1 (CDK1). Exposure of MDA-MB231 cells to NM also resulted in decreased transcription factor activities accompanied by the regulated phosphorylation of signalling molecules and a decrease in metalloproteinases, the principal modulators of the extracellular environment during cancer progression. Especially, inhibition of TGFβ-stimulated Smad2 phosphorylation and subsequent metastasis-related gene expression, and downregulation of ERK activity may be pivotal mechanisms underlying inhibitory effects of NM on NM inhibits lung metastasis of breast cancer cells and growth of colonized tumours in mice. Taken together, our data revealed that NM inhibits cell growth and metastasis of TNBC cells and indicated that NM is a multi-targeted drug that could be an adjunct therapy for TNBC treatment.

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Acknowledgements

This work was supported by a Korea Research Foundation Grant funded by the Ministry of Science, ICT, and Future Planning (MSIP; No. NRF-2016R1A2B1010036).

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Authors and Affiliations

  1. Department of Biomedical Sciences, College of Medicine, Korea University, 73 Inchon-ro, Seongbuk-gu, Seoul, 136-705, Republic of Korea

    Sunam Mander, Dong-Joo You, Sumi Park, Dong Hwi Kim, Hyo Jeong Yong, Jae Young Seong & Jong-Ik Hwang

  2. Department of HBP Surgery and Liver Transplantation, College of Medicine, Korea University, Seoul, Republic of Korea

    Dong-Sik Kim

  3. Transplantation Research Institute, Seoul National University, Yongun-dong, Jongno-gu, Seoul, 110-799, Republic of Korea

    Curie Ahn

  4. Molecular Imaging & Therapy Branch, Research Institute of National Cancer Center, Goyang, 10408, Republic of Korea

    Yun-Hee Kim

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  1. Sunam Mander
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Mander, S., You, DJ., Park, S. et al. Nafamostat mesilate negatively regulates the metastasis of triple-negative breast cancer cells. Arch. Pharm. Res. 41, 229–242 (2018). https://doi.org/10.1007/s12272-017-0996-9

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