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Inhibition of TGF-? signaling with halofuginone can enhance the antitumor effect
of irradiation in Lewis lung cancer
#MMPMID26664138
Lin R
; Yi S
; Gong L
; Liu W
; Wang P
; Liu N
; Zhao L
; Wang P
Onco Targets Ther
2015[]; 8
(?): 3549-59
PMID26664138
show ga
PURPOSE: It was reported that halofuginone has inhibitory effects on transforming
growth factor-beta (TGF-?) signaling pathway. The study was aimed to: 1) evaluate
the antitumor effects of halofuginone in combination with radiation therapy; and
2) preliminarily explore the possible mechanisms associated with these effects.
MATERIALS AND METHODS: Lewis lung cancer (LLC) cell lines and xenograft model
mice randomly received ionizing radiation, halofuginone, or combination
treatment. The changes associated with antitumor effect of halofuginone,
including hepatic and pulmonary metastases and survival, were observed. The
migratory and invasive capabilities of LLC cells were investigated by using
scratch assay and transwell chamber assay. The expression level of TGF-? and its
activation were assessed with enzyme-linked immunosorbent assay,
immunohistochemistry, and Western blotting. Chi-square test and survival analysis
were performed for statistical analysis. P<0.05 was regarded as statistically
significant. Unless otherwise specified, data were expressed as mean ± standard
deviation [Formula: see text]. RESULTS: After irradiation, the migratory and
invasive capabilities of LLC cells were strengthened, and the TGF-? pathway was
activated. The addition of halofuginone can significantly inhibit the migratory
and invasive trend induced by irradiation, and the TGF-? pathway was also
inhibited. In animal xenograft model, the addition of halofuginone to irradiation
inhibited the growth of subcutaneously implanted xenografts, reduced hepatic and
pulmonary metastases, and improved survival of the mice. The effect was
accompanied by a decrease in TGF-? levels. In addition, halofuginone inhibited
type I collagen expression and angiopoiesis. CONCLUSION: Halofuginone treatment
not only produces significant radiation-sensitizing effects but also inhibits
hepatic and pulmonary metastases. The underlying mechanisms of these phenomena
warrant additional studies.
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