Inhibition of Eph receptor A4 by 2,5-dimethylpyrrolyl benzoic acid suppresses human pancreatic cancer growing orthotopically in nude mice
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Hironobu Takano1, Toru Nakamura1, Takahiro Tsuchikawa1, Toshihiro Kushibiki1, Kouji Hontani1, Kazuho Inoko1, Mizuna Takahashi1, Shoki Sato1, Hirotake Abe1, Shintaro Takeuchi1, Nagato Sato1, Kei Hiraoka1, Hiroshi Nishihara2, Toshiaki Shichinohe1, Satoshi Hirano1
1Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
2Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
Toru Nakamura, e-mail: [email protected]
Keywords: EphA4, prognostic factor, 2,5-dimethylpyrrolyl benzoic acid, human pancreatic cancer, orthotopic models
Received: April 21, 2015 Accepted: September 20, 2015 Published: October 19, 2015
Ephrin receptor A4 (EphA4) is overexpressed in human pancreatic adenocarcinoma (PDAC) and activate cell growth. Recent studies have identified small molecules that block EphA4. In this study, we investigated the correlation between EphA4 expression and the prognosis of patients with PDAC. We also examined the cytostatic efficacy of 2,5-dimethylpyrrolyl benzoic acid (compound 1), a small molecule that blocks EphA4, in PDAC cells. Overall survival of patients with EphA4 positivity was significantly shorter than that of patients with EphA4 negativity (P = 0.029). In addition, multivariate analysis revealed that EphA4 expression was an independent prognostic factor in PDAC patients (P = 0.039). Compound 1 showed a cytostatic efficacy in PDAC cells expressing EphA4 in vitro and in vivo. Our study indicated that compound 1 suppressed both EphA4 and Akt phosphorylations, and induced apoptosis in PDAC cells expressing EphA4. In conclusion, compound 1 has a high potential as a therapeutic agent for patients with PDAC.
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