Anticancer activity of halofuginone in a preclinical model of osteosarcoma: inhibition of tumor growth and lung metastases
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Audrey Lamora1,2,3,4, Mathilde Mullard1,2,3, Jérôme Amiaud1,2,3, Régis Brion1,2,3, Dominique Heymann1,2,3, Françoise Redini1,2,3, Franck Verrecchia1,2,3
1INSERM, UMR 957, Equipe Labellisée Ligue contre le Cancer 2012, Nantes, France
2Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France
3CHU Hôtel Dieu, Nantes, France
4Inserm Liliane Bettencourt School, France
Franck Verrecchia, e-mail: [email protected]
Keywords: halofuginone, osteosarcoma, TGF-β, metastases, bone remodeling
Received: February 04, 2015 Accepted: April 24, 2015 Published: May 07, 2015
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.
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