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

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.

• Authors: Naito Kurio, Tsuyoshi Shimo, Takuya Fukazawa, Munenori Takaoka, Tatsuo Okui, Nur Mohammad Monsur Hassan, Tatsuki Honami, Shinji Hatakeyama, Masahiko Ikeda, Yoshio Naomoto, Akira Sasaki
• Journal: Experimental cell research (Exp Cell Res) Vol. 317 Issue 8 Pg. 1134-46 (May 01 2011) ISSN: 1090-2422 [Electronic] United States
• PMID: 21338601 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Morpholines
• Parathyroid Hormone-Related Protein
• RANK Ligand
• TAE226
• Receptor, IGF Type 1
• Focal Adhesion Protein-Tyrosine Kinases

Topics

• Animals
• Bone Neoplasms (metabolism, pathology, secondary)
• Breast Neoplasms (drug therapy, pathology)
• Cell Line
• Cells, Cultured
• Female
• Focal Adhesion Protein-Tyrosine Kinases (antagonists & inhibitors, genetics)
• Humans
• Macrophages (cytology, drug effects, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Nude
• Morpholines (pharmacology, therapeutic use)
• Neoplasm Metastasis
• Neoplasm Transplantation
• Osteoclasts (cytology, drug effects, metabolism)
• Parathyroid Hormone-Related Protein (metabolism)
• RANK Ligand (metabolism)
• Receptor, IGF Type 1 (antagonists & inhibitors, genetics)
• Stromal Cells (cytology, metabolism)