Anti-tumor effect in human breast cancer by TAE226, a dual inhibitor for FAX and IGF-IR in vitro and in vivo

作者：Kurio Naito; Shimo Tsuyoshi^*; Fukazawa Takuya; Takaoka Munenori; Okui Tatsuo; Hassan Nur Mohammad Monsur; Honami Tatsuki; Hatakeyama Shinji; Ikeda Masahiko; Naomoto Yoshio; Sasaki Akira

来源：Experimental Cell Research, 2011, 317(8): 1134-1146.

DOI：10.1016/j.yexcr.2011.02.008

• Focal adhesion kinase
• Bone metastasis
• Bone resorption

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.

• 出版日期2011-5-1