title: 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.affiliation: Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Okayama, Japan.
authors.forename: Naito
authors.initials: N
authors.lastname: Kurio
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shimo
authors.forename: Takuya
authors.initials: T
authors.lastname: Fukazawa
authors.forename: Munenori
authors.initials: M
authors.lastname: Takaoka
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Okui
authors.forename: Nur Mohammad Monsur
authors.initials: NM
authors.lastname: Hassan
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Honami
authors.forename: Shinji
authors.initials: S
authors.lastname: Hatakeyama
authors.forename: Masahiko
authors.initials: M
authors.lastname: Ikeda
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Naomoto
authors.forename: Akira
authors.initials: A
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use*; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D009025:Morpholines; D044162:Parathyroid Hormone-Related Protein; D053245:RANK Ligand; C524632:TAE226; D017526:Receptor, IGF Type 1; D051416:Focal Adhesion Protein-Tyrosine Kinases