Lamora, A., Mullard, M., Amiaud, J. et al. (4 more authors) (2015) Anticancer activity of halofuginone in a preclinical model of osteosarcoma: inhibition of tumor growth and lung metastases. Oncotarget, 6 (16). pp. 14413-14427. ISSN 1949-2553
Abstract
Osteosarcoma is the main malignant primary bone tumor in children and adolescents for whom the prognosis remains poor, especially when metastases are present at diagnosis. Because we recently demonstrated that TGF-β/Smad cascade plays a crucial role in osteosarcoma metastatic progression, we investigated the effect of halofuginone, identified as an inhibitor of the TGF-β/Smad3 cascade, on osteosarcoma progression. A preclinical model of osteosarcoma was used to evaluate the impact of halofuginone on tumor growth, tumor microenvironment and metastasis development. In vivo experiments showed that halofuginone reduces primary tumor growth and lung metastases development. In vitro experiments demonstrated that halofuginone decreases cell viability mainly by its ability to induce caspase-3 dependent cell apoptosis. Moreover, halofuginone inhibits the TGF-β/Smad3 cascade and the response of TGF-β key targets involved in the metastases dissemination process such as MMP-2. In addition, halofuginone treatment affects the "vicious cycle" established between tumor and bone cells, and therefore the tumor-associated bone osteolysis. Together, these results demonstrate that halofuginone decreased primary osteosarcoma development and associated lung metastases by targeting both the tumor cells and the tumor microenvironment. Using halofuginone may be a promising therapeutic strategy against tumor progression of osteosarcoma specifically against lung metastases dissemination.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2015 Impact Journals. All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License. |
Keywords: | halofuginone; osteosarcoma; TGF-beta; metastases; bone remodeling |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 13 Apr 2016 08:24 |
Last Modified: | 30 Aug 2019 13:22 |
Published Version: | http://dx.doi.org/10.18632/oncotarget.3891 |
Status: | Published |
Publisher: | Impact Journals |
Refereed: | Yes |
Identification Number: | 10.18632/oncotarget.3891 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:98147 |