| RRC ID |
18507
|
| 著者 |
Kurio N, Shimo T, Fukazawa T, Takaoka M, Okui T, Hassan NM, Honami T, Hatakeyama S, Ikeda M, Naomoto Y, Sasaki A.
|
| タイトル |
Anti-tumor effect in human breast cancer by TAE226, a dual inhibitor for FAK and IGF-IR in vitro and in vivo.
|
| ジャーナル |
Exp Cell Res
|
| Abstract |
Focal adhesion kinase (FAK) is a 125-kDa non-receptor type tyrosine kinase that localizes to focal adhesions. FAK 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 FAK 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 κ 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 FAK 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.
|
| 巻・号 |
317(8)
|
| ページ |
1134-46
|
| 公開日 |
2011-5-1
|
| DOI |
10.1016/j.yexcr.2011.02.008
|
| PII |
S0014-4827(11)00059-0
|
| PMID |
21338601
|
| MeSH |
Animals
Bone Neoplasms / metabolism
Bone Neoplasms / pathology
Bone Neoplasms / secondary
Breast Neoplasms / drug therapy*
Breast Neoplasms / pathology
Cell Line
Cells, Cultured
Female
Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors*
Focal Adhesion Protein-Tyrosine Kinases / genetics
Humans
Macrophages / cytology
Macrophages / drug effects
Macrophages / metabolism
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Nude
Morpholines / pharmacology
Morpholines / therapeutic use*
Neoplasm Metastasis
Neoplasm Transplantation
Osteoclasts / cytology
Osteoclasts / drug effects
Osteoclasts / metabolism
Parathyroid Hormone-Related Protein / metabolism
RANK Ligand / metabolism
Receptor, IGF Type 1 / antagonists & inhibitors*
Receptor, IGF Type 1 / genetics
Stromal Cells / cytology
Stromal Cells / metabolism
|
| IF |
3.383
|
| 引用数 |
27
|
|
WOS 分野
|
ONCOLOGY
CELL BIOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
ST2(RCB0224)
RAW 264(RCB0535) |
