RRC ID 62253
Author Takano H, Nakamura T, Tsuchikawa T, Kushibiki T, Hontani K, Inoko K, Takahashi M, Sato S, Abe H, Takeuchi S, Sato N, Hiraoka K, Nishihara H, Shichinohe T, Hirano S.
Title Inhibition of Eph receptor A4 by 2,5-dimethylpyrrolyl benzoic acid suppresses human pancreatic cancer growing orthotopically in nude mice.
Journal Oncotarget
Abstract 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.
Volume 6(38)
Pages 41063-76
Published 2015-12-1
DOI 10.18632/oncotarget.5729
PII 5729
PMID 26516928
PMC PMC4747390
MeSH Adenocarcinoma / drug therapy* Adenocarcinoma / genetics Adenocarcinoma / metabolism Adult Aged Aged, 80 and over Animals Benzoates / pharmacology* Benzoic Acid / chemistry Benzoic Acid / pharmacology* Blotting, Western Cell Line, Tumor Cell Proliferation / drug effects Female Gene Expression Regulation, Neoplastic / drug effects Humans Immunohistochemistry Kaplan-Meier Estimate Male Mice, Inbred BALB C Mice, Nude Middle Aged Pancreatic Neoplasms / drug therapy* Pancreatic Neoplasms / genetics Pancreatic Neoplasms / metabolism Proto-Oncogene Proteins c-akt / metabolism Pyrroles / chemistry Receptor, EphA4 / antagonists & inhibitors* Receptor, EphA4 / genetics Receptor, EphA4 / metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction / drug effects Xenograft Model Antitumor Assays*
IF 5.168
Resource
Human and Animal Cells HS-K(RCB0159)