Patricia Juárez, Khalid S. Mohammad, Juan Juan Yin, Pierrick G. J. Fournier, Ryan C. McKenna, Holly W Davis, Xiang H. Peng, Maria Niewolna, Delphine Javelaud, John M Chirgwin, Alain Mauviel, and Theresa A. Guise
Transforming growth factor (TGF-β) derived from bone fuels melanoma bone metastases by inducing tumor secretion of pro-metastatic factors that act on bone cells to change the skeletal microenvironment. Halofuginone is a plant alkaloid derivative that blocks TGF-β signaling with antiangiogenic and antiproliferative properties. Here, we demonstrate for the first time that halofuginone therapy decreases development and progression of bone metastasis caused by melanoma cells through inhibition of TGF-β signaling. Halofuginone treatment of human melanoma cells inhibited cell proliferation, phosphorylation of SMAD proteins in response to TGF-β, and TGF-β-induced SMAD-driven transcription. In addition, halofuginone reduced expression of TGF-β target genes that enhance bone metastases, including PTHrP, CTGF, CXCR4, and IL11. Also, cell apoptosis was increased in response to halofuginone. In nude mice inoculated with 1205Lu melanoma cells, a preventive protocol with halofuginone inhibited bone metastasis. The beneficial effects of halofuginone treatment were comparable to those observed with other anti-TGF-β strategies, including systemic administration of SD208, a small molecule inhibitor of TGF-β receptor I kinase, or forced overexpression of Smad7, a negative regulator of TGF-β signaling. Furthermore, mice with established bone metastases treated with halofuginone had significantly less osteolysis than mice receiving placebo assessed by radiographys. Thus, halofuginone is also effective in reducing the progression of melanoma bone metastases. Moreover, halofuginone treatment reduced melanoma metastasis to the brain, showing the potential of this novel treatment against cancer metastasis.