title: Inhibition of Eph receptor A4 by 2,5-dimethylpyrrolyl benzoic acid suppresses human pancreatic cancer growing orthotopically in nude mice.
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.
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Takano
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tsuchikawa
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kushibiki
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Hontani
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Kazuho
authors.initials: K
authors.lastname: Inoko
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Mizuna
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Shoki
authors.initials: S
authors.lastname: Sato
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Hirotake
authors.initials: H
authors.lastname: Abe
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Takeuchi
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Nagato
authors.initials: N
authors.lastname: Sato
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Hiraoka
authors.affiliation: Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishihara
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Shichinohe
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirano
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D019817:Benzoic Acid / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry; D036122:Receptor, EphA4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C000611121:2,5-dimethylpyrrolylbenzoic acid; D001565:Benzoates; D011758:Pyrroles; D019817:Benzoic Acid; D036122:Receptor, EphA4; D051057:Proto-Oncogene Proteins c-akt; C067286:2,5-dimethylpyrrole
keywords: 2,5-dimethylpyrrolyl benzoic acid; EphA4; human pancreatic cancer; orthotopic models; prognostic factor