Anti-tumor effect in human breast cancer by TAE226, a dual inhibitor for FAX and IGF-IR in vitro and in vivo
Anti-tumor effect in human breast cancer by TAE226, a dual inhibitor for FAX and IGF-IR in vitro and in vivo
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DOI：
10.1016/j.yexcr.2011.02.008
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发表时间：
2011-05-01
影响因子：
3.7
通讯作者：
Sasaki, Akira
中科院分区：
文献类型：
--
作者：
Kurio, Naito;Shimo, Tsuyoshi;Sasaki, Akira
粘着斑激酶（FAR）是一种125 kDa的非受体型酪氨酸激酶，定位于粘着斑。FAR过表达常见于乳腺浸润性和转移性癌。结肠、甲状腺和前列腺，但其在溶骨性转移中的作用尚不清楚。在这项研究中，我们分析了新的FAR Tyr（397）抑制剂TAE 226对乳腺癌骨转移的抗肿瘤作用。小鼠经口给予TAE 226可显著降低MDA-MB-231乳腺癌细胞诱导的骨转移和参与的破骨细胞，并提高骨转移小鼠模型的存活率。TAE 226还抑制体内皮下肿瘤的生长和体外MDA-MB-231细胞的增殖和迁移。值得注意的是，TAE 226抑制小鼠前破骨细胞RAW 264.7细胞中的破骨细胞形成，以及成熟破骨细胞中的肌动蛋白环和小窝形成。此外，TAE 226抑制骨基质ST 2细胞中甲状旁腺素相关蛋白（PTHrP）诱导的核因子κ B配体（RANKL）受体激活剂基因表达，并抑制体内PTHrP给药诱导的血液游离钙浓度。这些发现表明，FAR在溶骨性转移中起重要作用，并且在肿瘤、前破骨细胞、成熟破骨细胞和骨基质细胞中被激活，并且TAE 226可以有效地用于治疗癌症诱导的骨转移和其他骨疾病。(C)2011 Elsevier Inc. All rights reserved.
Focal adhesion kinase (FAR) is a 125-kDa non-receptor type tyrosine kinase that localizes to focal adhesions. FAR overexpression is frequently found in invasive and metastatic cancers of the breast. colon, thyroid, and prostate, but its role in osteolytic metastasis is not well understood. In this study, we have analyzed anti-tumor effects of the novel FAR Tyr(397) inhibitor TAE226 against bone metastasis in breast cancer by using TAE226. Oral administration of TAE226 in mice significantly decreased bone metastasis and osteoclasts involved which were induced by MDA-MB-231 breast cancer cells and increased the survival rate of the mouse models of bone metastasis. TAE226 also suppressed the growth of subcutaneous tumors in vivo and the proliferation and migration of MDA-MB-231 cells in vitro. Significantly, TAE226 inhibited the osteoclast formation in murine pre-osteoclastic RAW264.7 cells, and actin ring and pit formation in mature osteoclasts. Moreover, TAE226 inhibited the receptor activator for nuclear factor kappa B Ligand (RANKL) gene expression induced by parathyroid hormone-related protein (PTHrP) in bone stromal ST2 cells and blood free calcium concentration induced by PTHrP administration in vivo. These findings suggest that FAR was critically involved in osteolytic metastasis and activated in tumors, pre-osteoclasts, mature osteoclasts, and bone stromal cells and TAE226 can be effectively used for the treatment of cancer induced bone metastasis and other bone diseases. (C) 2011 Elsevier Inc. All rights reserved.