RRC ID 18507
Author Kurio N, Shimo T, Fukazawa T, Takaoka M, Okui T, Hassan NM, Honami T, Hatakeyama S, Ikeda M, Naomoto Y, Sasaki A.
Title Anti-tumor effect in human breast cancer by TAE226, a dual inhibitor for FAK and IGF-IR in vitro and in vivo.
Journal 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.
Volume 317(8)
Pages 1134-46
Published 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
Times Cited 27
Human and Animal Cells ST2(RCB0224) RAW 264(RCB0535)