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2017 ; 8
(49
): 86447-86462
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Halofuginone inhibits TGF-?/BMP signaling and in combination with zoledronic acid
enhances inhibition of breast cancer bone metastasis
#MMPMID29156807
Juárez P
; Fournier PGJ
; Mohammad KS
; McKenna RC
; Davis HW
; Peng XH
; Niewolna M
; Mauviel A
; Chirgwin JM
; Guise TA
Oncotarget
2017[Oct]; 8
(49
): 86447-86462
PMID29156807
show ga
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? and
BMP-signaling. Halofuginone blocked TGF-?-signaling in MDA-MB-231 and PC3 cells
showed by inhibition of TGF-?-induced Smad-reporter, phosphorylation of
Smad-proteins, and expression of TGF-?-regulated metastatic genes. Halofuginone
increased inhibitory Smad7-mRNA and reduced TGF-?-receptor II protein. Proline
supplementation but not Smad7-knockdown reversed halofuginone-inhibition of
TGF-?-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.
free
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