title: Halofuginone inhibits the establishment and progression of melanoma bone metastases.
abstract: TGF-β derived from bone fuels melanoma bone metastases by inducing tumor secretion of prometastatic 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 show for the first time that halofuginone therapy decreases development and progression of bone metastasis caused by melanoma cells through the 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 1205 Lu melanoma cells, a preventive protocol with halofuginone inhibited bone metastasis. The beneficial effects of halofuginone treatment were comparable with 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 radiography. 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.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Indiana University-Purdue University Indianapolis, Walther Hall, C132 980 W Walnut Street, Indianapolis, IN 46202, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Juárez
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Mohammad
authors.forename: Juan Juan
authors.initials: JJ
authors.lastname: Yin
authors.forename: Pierrick G J
authors.initials: PG
authors.lastname: Fournier
authors.forename: Ryan C
authors.initials: RC
authors.lastname: McKenna
authors.forename: Holly W
authors.initials: HW
authors.lastname: Davis
authors.forename: Xiang H
authors.initials: XH
authors.lastname: Peng
authors.forename: Maria
authors.initials: M
authors.lastname: Niewolna
authors.forename: Delphine
authors.initials: D
authors.lastname: Javelaud
authors.forename: John M
authors.initials: JM
authors.lastname: Chirgwin
authors.forename: Alain
authors.initials: A
authors.lastname: Mauviel
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Guise
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D010880:Piperidines / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D052999:Quinazolinones; C010176:halofuginone