期刊
ONCOTARGET
卷 8, 期 49, 页码 86447-86462出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.21200
关键词
halofuginone; zoledronic acid; bone metastases; TGF-beta; BMP
资金
- NIH [R01CA69158, R01DK067333, R01DK065837, U01CA143057]
- Mary Kay Ash Foundation
- V-Foundation
- Aurbach Endowment of the University of Virginia
- Indiana University
- Indiana Economic Development Fund
- Susan Komen Foundation
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 TGF beta and BMP-signaling. Halofuginone blocked TGF-beta-signaling in MDA-MB-231 and PC3 cells showed by inhibition of TGF-beta-induced Smad-reporter, phosphorylation of Smad-proteins, and expression of TGF-beta-regulated metastatic genes. Halofuginone increased inhibitory Smad7-mRNA and reduced TGF-beta-receptor II protein. Proline supplementation but not Smad7-knockdown reversed halofuginone-inhibition of TGF-beta-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 orthotopictumors. 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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