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Tetrahydrofurofuran-type lignans inhibit breast cancer-mediated bone destruction by blocking the vicious cycle between cancer cells, osteoblasts and osteoclasts

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Summary

Breast cancer frequently spreads to bone. The interaction between bone metastases and microenvironment, referred as the “vicious cycle”, increases both tumor burden and bone destruction. Therefore, inhibition at any point in this “vicious cycle” can reduce malignant osteolytic lesions in patients with advanced breast cancer. In this study, we evaluated whether tetrahydrofurofuran-type lignans derived from Magnoliae Flos, commonly used in traditional Asian medicine to treat inflammatory diseases, could block breast cancer-mediated bone loss. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin at noncytotoxic concentrations suppressed mRNA expression and secretion of osteolytic factor PTHrP in MDA-MB-231 metastatic human breast cancer cells. Fargesin inhibited TGF-β-stimulated cell viability, migration, and invasion and decreased TGF-β-induced PTHrP production in MDA-MB-231 cells. In addition, these lignans reduced RANKL/OPG ratio in PTHrP-treated hFOB1.19 human osteoblastic cells and inhibited RANKL-mediated osteoclast differentiation in mouse bone marrow macrophages. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin substantially reduced bone-resorbing activity of osteoclasts by inhibiting MMP-9 and cathepsin K activities. Furthermore, orally administered fargesin inhibited tumor growth and cancer-mediated bone destruction in mice with MDA-MB-231 cells injected into calvarial tissues. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin blocked initiation and progression of the “vicious cycle” between breast cancer metastases and bone microenvironment by inhibiting PTHrP production in breast cancer cells and osteoclastic bone resorption. Therefore, these tetrahydrofurofuran-type lignans have the potential to serve as beneficial agents to prevent and treat cancer-induced bone destruction in breast cancer patients.

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Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010–0026040).

Declaration of interests

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, 120-749, Republic of Korea

    Ah Young Jun, Hyun-Jeong Kim, Kwang-Kyun Park & Won-Yoon Chung

  2. Department of Oral Biology, Oral Cancer Research Institute, and Brain Korea 21 Project, Yonsei University College of Dentistry, Seoul, 120-752, Republic of Korea

    Ah Young Jun, Hyun-Jeong Kim, Kwang-Kyun Park & Won-Yoon Chung

  3. Department of Life Science, Andong National University, Andong, 760-740, Republic of Korea

    Kun Ho Son & Dong Hwa Lee

  4. College of Pharmacy, Catholic University of Daegu, Gyeongsan, 712-702, Republic of Korea

    Mi-Hee Woo

  5. Department of Oral Biology, Yonsei University, College of Dentistry, 50 Yonsei-ro, Seodaemoon-Ku, Seoul, 120-752, Republic of Korea

    Won-Yoon Chung

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  1. Ah Young Jun
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Correspondence to Won-Yoon Chung.

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Jun, A.Y., Kim, HJ., Park, KK. et al. Tetrahydrofurofuran-type lignans inhibit breast cancer-mediated bone destruction by blocking the vicious cycle between cancer cells, osteoblasts and osteoclasts. Invest New Drugs 32, 1–13 (2014). https://doi.org/10.1007/s10637-013-9969-0

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