Halofuginone inhibits TGF-β/BMP signaling and in combination with zoledronic acid enhances inhibition of breast cancer bone metastasis
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Patricia Juárez1,2, Pierrick G.J. Fournier1,2, Khalid S. Mohammad1, Ryan C. McKenna3, Holly W. Davis3, Xiang H. Peng1, Maria Niewolna1, Alain Mauviel4,5,6,7 John M. Chirgwin1 and Theresa A. Guise1
1Division of Endocrinology, Department of Medicine, Indiana University Purdue University at Indianapolis, Indiana, USA
2Ensenada Center for Scientific Research and Higher Education, Ensenada, Mexico
3University of Virginia, Charlottesville, Virginia, USA
4Institute Curie, Orsay, France
5INSERM U1021, Orsay, France
6CNRS UMR3347, Orsay, France
7Université Paris XI, Orsay, France
Theresa A. Guise, email: [email protected]
Keywords: halofuginone, zoledronic acid, bone metastases, TGF-β, BMP
Received: June 21, 2017 Accepted: August 04, 2017 Published: September 23, 2017
More efficient therapies that target multiple molecular mechanisms are needed for the treatment of incurable bone metastases. Halofuginone is a plant alkaloid-derivative with antiangiogenic and antiproliferative effects. Here we demonstrate that halofuginone is an effective therapy for the treatment of bone metastases, through multiple actions that include inhibition of TGFβ and BMP-signaling.
Halofuginone blocked TGF-β-signaling in MDA-MB-231 and PC3 cells showed by inhibition of TGF-β-induced Smad-reporter, phosphorylation of Smad-proteins, and expression of TGF-β-regulated metastatic genes. Halofuginone increased inhibitory Smad7-mRNA and reduced TGF-β-receptor II protein. Proline supplementation but not Smad7-knockdown reversed halofuginone-inhibition of TGF-β-signaling. Halofuginone also decreased BMP-signaling. Treatment of MDA-MB-231 and PC3 cells with halofuginone reduced the BMP-Smad-reporter (BRE)4, Smad1/5/8-phosphorylation and mRNA of the BMP-regulated gene Id-1. Halofuginone decreased immunostaining of phospho-Smad2/3 and phospho-Smad1/5/8 in cancer cells in vivo.
Furthermore, halofuginone decreased tumor-take and growth of orthotopic-tumors. Mice with breast or prostate bone metastases treated with halofuginone had significantly less osteolysis than control mice. Combined treatment with halofuginone and zoledronic-acid significantly reduced osteolytic area more than either treatment alone. Thus, halofuginone reduces breast and prostate cancer bone metastases in mice and combined with treatment currently approved by the FDA is an effective treatment for this devastating complication of breast and prostate-cancer.
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