Halofuginone inhibits the establishment and progression of melanoma bone metastases.
Halofuginone inhibits the establishment and progression of melanoma bone metastases.
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DOI：
10.1158/0008-5472.can-12-1444
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发表时间：
2012-12-01
期刊：
影响因子：
11.2
通讯作者：
Guise TA
中科院分区：
文献类型：
--
作者：
Juárez P;Mohammad KS;Yin JJ;Fournier PG;McKenna RC;Davis HW;Peng XH;Niewolna M;Javelaud D;Chirgwin JM;Mauviel A;Guise TA
源自骨的转化生长因子（TGF-β）通过诱导肿瘤分泌促转移因子，作用于骨细胞改变骨骼微环境，从而促进黑色素瘤骨转移。 Halofuginone 是一种植物生物碱衍生物，可阻断 TGF-β 信号传导，具有抗血管生成和抗增殖特性。在这里，我们首次证明卤常酮疗法通过抑制 TGF-β 信号传导来减少黑色素瘤细胞引起的骨转移的发生和进展。 Halofuginone 处理人黑色素瘤细胞可抑制细胞增殖、响应 TGF-β 的 SMAD 蛋白磷酸化以及 TGF-β 诱导的 SMAD 驱动的转录。此外，卤常酮还能降低促进骨转移的 TGF-β 靶基因的表达，包括 PTHrP、CTGF、CXCR4 和 IL11。此外，对卤常酮的反应增加了细胞凋亡。在接种 1205Lu 黑色素瘤细胞的裸鼠中，卤常酮预防方案抑制了骨转移。卤常酮治疗的有益效果与其他抗 TGF-β 策略观察到的有益效果相当，包括全身给药 SD208（TGF-β 受体 I 激酶的小分子抑制剂）或强制过度表达 Smad7（TGF-β 信号传导的负调节因子）。此外，通过放射线照相评估，与接受安慰剂的小鼠相比，用卤常酮治疗的已发生骨转移的小鼠的骨质溶解明显减少。因此，卤常酮也能有效减少黑色素瘤骨转移的进展。此外，卤常酮治疗减少了黑色素瘤向大脑的转移，显示了这种新疗法对抗癌症转移的潜力。
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.