Dual tyrosine kinase inhibitor for focal adhesion kinase and insulin-like growth factor-I receptor exhibits anticancer effect in esophageal adenocarcinoma in vitro and in vivo.

Abstract

PURPOSE:

Focal adhesion kinase (FAK) regulates integrin and growth factor-mediated signaling pathways to enhance cell migration, proliferation, and survival, and its up-regulation correlates malignant grade and poor outcome in several types of cancer. In this study, we aimed to raise a potential therapeutic strategy using a FAK inhibitor for Barrett's esophageal adenocarcinoma.

EXPERIMENTAL DESIGN:

The expression status of FAK in clinical Barrett's esophageal adenocarcinoma tissues was determined by immunohistochemistry. Cultured esophageal adenocarcinoma cells were treated with TAE226, a specific FAK inhibitor with an additional effect of inhibiting insulin-like growth factor-I receptor (IGF-IR), to assess its anticancer effect in vitro. Western blot was carried out to explore a participating signaling pathway for TAE226-induced cell death. Furthermore, TAE226 was orally administered to s.c. xenograft animals to investigate its anticancer effect in vivo.

RESULTS:

Strong expression of FAK was found in 94.0% of Barrett's esophageal adenocarcinoma compared with 17.9% of Barrett's epithelia, suggesting that FAK might play a critical role in the progression of Barrett's esophageal adenocarcinoma. When esophageal adenocarcinoma cells were treated with TAE226, cell proliferation and migration were greatly inhibited with an apparent structural change of actin fiber and a loss of cell adhesion. The activities of FAK, IGF-IR, and AKT were suppressed by TAE226 and subsequent dephosphorylation of BAD at Ser(136) occurred, resulting in caspase-mediated apoptosis. In vivo tumor volume was significantly reduced by oral administration of TAE226.

CONCLUSIONS:

These results suggest that TAE226, a dual tyrosine kinase inhibitor for FAK and IGF-IR, could become a new remedy for Barrett's esophageal adenocarcinoma.

• Authors: Nobuyuki Watanabe, Munenori Takaoka, Kazufumi Sakurama, Yasuko Tomono, Shinji Hatakeyama, Osamu Ohmori, Takayuki Motoki, Yasuhiro Shirakawa, Tomoki Yamatsuji, Minoru Haisa, Junji Matsuoka, David G Beer, Hitoshi Nagatsuka, Noriaki Tanaka, Yoshio Naomoto
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 14 Pg. 4631-9 (Jul 15 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18628478 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Morpholines
• TAE226
• Receptor, IGF Type 1
• Focal Adhesion Protein-Tyrosine Kinases

Topics

• Adenocarcinoma (drug therapy, enzymology)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Movement (drug effects)
• Cells, Cultured
• Enzyme Inhibitors (pharmacology)
• Esophageal Neoplasms (drug therapy, enzymology)
• Flow Cytometry
• Fluorescent Antibody Technique
• Focal Adhesion Protein-Tyrosine Kinases (antagonists & inhibitors)
• Humans
• Immunohistochemistry
• In Situ Nick-End Labeling
• Mice
• Morpholines (pharmacology)
• Receptor, IGF Type 1 (antagonists & inhibitors)
• Signal Transduction (drug effects)