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

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

Research output: Contribution to journalArticle

29 Citations (Scopus)

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 Tyr397 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.

Original languageEnglish
Pages (from-to)1134-1146
Number of pages13
JournalExperimental Cell Research
Volume317
Issue number8
DOIs
Publication statusPublished - May 1 2011

Fingerprint

Focal Adhesion Protein-Tyrosine Kinases
Osteoclasts
Breast Neoplasms
Neoplasm Metastasis
Bone and Bones
Neoplasms
Parathyroid Hormone-Related Protein
Stromal Cells
Bone Neoplasms
Focal Adhesions
Bone Diseases
Cytoplasmic and Nuclear Receptors
In Vitro Techniques
TAE226
Protein-Tyrosine Kinases
Colonic Neoplasms
Oral Administration
Actins
Prostate
Cell Survival

Keywords

  • Bone metastasis
  • Bone resorption
  • Focal adhesion kinase

ASJC Scopus subject areas

  • Cell Biology

Cite this

Anti-tumor effect in human breast cancer by TAE226, a dual inhibitor for FAK and IGF-IR in vitro and in vivo. / Kurio, Naito; Shimo, Tsuyoshi; Fukazawa, Takuya; Takaoka, Munenori; Okui, Tatsuo; Hassan, Nur Mohammad Monsur; Honami, Tatsuki; Hatakeyama, Shinji; Ikeda, Masahiko; Naomoto, Yoshio; Sasaki, Akira.

In: Experimental Cell Research, Vol. 317, No. 8, 01.05.2011, p. 1134-1146.

Research output: Contribution to journalArticle

Kurio, N, Shimo, T, Fukazawa, T, Takaoka, M, Okui, T, Hassan, NMM, Honami, T, Hatakeyama, S, Ikeda, M, Naomoto, Y & Sasaki, A 2011, 'Anti-tumor effect in human breast cancer by TAE226, a dual inhibitor for FAK and IGF-IR in vitro and in vivo', Experimental Cell Research, vol. 317, no. 8, pp. 1134-1146. https://doi.org/10.1016/j.yexcr.2011.02.008
Kurio, Naito ; Shimo, Tsuyoshi ; Fukazawa, Takuya ; Takaoka, Munenori ; Okui, Tatsuo ; Hassan, Nur Mohammad Monsur ; Honami, Tatsuki ; Hatakeyama, Shinji ; Ikeda, Masahiko ; Naomoto, Yoshio ; Sasaki, Akira. / Anti-tumor effect in human breast cancer by TAE226, a dual inhibitor for FAK and IGF-IR in vitro and in vivo. In: Experimental Cell Research. 2011 ; Vol. 317, No. 8. pp. 1134-1146.
@article{6b76f6c065b74b098da3fd05898f54a8,
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 Tyr397 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.",
keywords = "Bone metastasis, Bone resorption, Focal adhesion kinase",
author = "Naito Kurio and Tsuyoshi Shimo and Takuya Fukazawa and Munenori Takaoka and Tatsuo Okui and Hassan, {Nur Mohammad Monsur} and Tatsuki Honami and Shinji Hatakeyama and Masahiko Ikeda and Yoshio Naomoto and Akira Sasaki",
year = "2011",
month = "5",
day = "1",
doi = "10.1016/j.yexcr.2011.02.008",
language = "English",
volume = "317",
pages = "1134--1146",
journal = "Experimental Cell Research",
issn = "0014-4827",
publisher = "Academic Press Inc.",
number = "8",

}

TY - JOUR

T1 - Anti-tumor effect in human breast cancer by TAE226, a dual inhibitor for FAK and IGF-IR in vitro and in vivo

AU - Kurio, Naito

AU - Shimo, Tsuyoshi

AU - Fukazawa, Takuya

AU - Takaoka, Munenori

AU - Okui, Tatsuo

AU - Hassan, Nur Mohammad Monsur

AU - Honami, Tatsuki

AU - Hatakeyama, Shinji

AU - Ikeda, Masahiko

AU - Naomoto, Yoshio

AU - Sasaki, Akira

PY - 2011/5/1

Y1 - 2011/5/1

N2 - 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 Tyr397 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.

AB - 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 Tyr397 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.

KW - Bone metastasis

KW - Bone resorption

KW - Focal adhesion kinase

UR - http://www.scopus.com/inward/record.url?scp=79953078588&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79953078588&partnerID=8YFLogxK

U2 - 10.1016/j.yexcr.2011.02.008

DO - 10.1016/j.yexcr.2011.02.008

M3 - Article

C2 - 21338601

AN - SCOPUS:79953078588

VL - 317

SP - 1134

EP - 1146

JO - Experimental Cell Research

JF - Experimental Cell Research

SN - 0014-4827

IS - 8

ER -