title: Enalapril and ASS inhibit tumor growth in a transgenic mouse model of islet cell tumors.
abstract: Accumulating evidence suggests a role for angiotensin-converting enzymes involving the angiotensin II-receptor 1 (AT1-R) and the cyclooxygenase pathway in carcinogenesis. The effects of ASS and enalapril were assessed in vitro and in a transgenic mouse model of pancreatic neuroendocrine neoplasms (pNENs). The effects of enalapril and ASS on proliferation and expression of the AGTR1A and its target gene vascular endothelial growth factor (Vegfa) were assessed in the neuroendocrine cell line BON1. Rip1-Tag2 mice were treated daily with either 0.6 mg/kg bodyweight of enalapril i.p., 20 mg/kg bodyweight of ASS i.p., or a vehicle in a prevention (weeks 5-12) and a survival group (week 5 till death). Tumor surface, weight of pancreatic glands, immunostaining for AT1-R and nuclear factor kappa beta (NFKB), and mice survival were analyzed. In addition, sections from human specimens of 20 insulinomas, ten gastrinomas, and 12 non-functional pNENs were evaluated for AT1-R and NFKB (NFKB1) expression and grouped according to the current WHO classification. Proliferation was significantly inhibited by enalapril and ASS in BON1 cells, with the combination being the most effective. Treatment with enalapril and ASS led to significant downregulation of known target genes Vegf and Rela at RNA level. Tumor growth was significantly inhibited by enalapril and ASS in the prevention group displayed by a reduction of tumor size (84%/67%) and number (30%/45%). Furthermore, daily treatment with enalapril and ASS prolonged the overall median survival compared with vehicle-treated Rip1-Tag2 (107 days) mice by 9 and 17 days (P=0.016 and P=0.013). The AT1-R and the inflammatory transcription factor NFKB were abolished completely upon enalapril and ASS treatment. AT1-R and NFKB expressions were observed in 80% of human pNENs. Enalapril and ASS may provide an approach for chemoprevention and treatment of pNENs.
authors.affiliation: Department of General SurgeryEndocrine Center, University Hospital Giessen and Marburg, Campus Marburg, Baldingerstrasse, 35043 Marburg, GermanyDepartment of General SurgeryUniversity Hospital Giessen and Marburg, Campus Giessen, Rudolf-Buchheim-Strasse 7, 35385 Giessen, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Fendrich
authors.affiliation: Department of General SurgeryEndocrine Center, University Hospital Giessen and Marburg, Campus Marburg, Baldingerstrasse, 35043 Marburg, GermanyDepartment of General SurgeryUniversity Hospital Giessen and Marburg, Campus Giessen, Rudolf-Buchheim-Strasse 7, 35385 Giessen, Germany.
authors.forename: C L
authors.initials: CL
authors.lastname: Lopez
authors.affiliation: Department of General SurgeryEndocrine Center, University Hospital Giessen and Marburg, Campus Marburg, Baldingerstrasse, 35043 Marburg, GermanyDepartment of General SurgeryUniversity Hospital Giessen and Marburg, Campus Giessen, Rudolf-Buchheim-Strasse 7, 35385 Giessen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Manoharan
authors.affiliation: Department of General SurgeryEndocrine Center, University Hospital Giessen and Marburg, Campus Marburg, Baldingerstrasse, 35043 Marburg, GermanyDepartment of General SurgeryUniversity Hospital Giessen and Marburg, Campus Giessen, Rudolf-Buchheim-Strasse 7, 35385 Giessen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Maschuw
authors.affiliation: Department of General SurgeryEndocrine Center, University Hospital Giessen and Marburg, Campus Marburg, Baldingerstrasse, 35043 Marburg, GermanyDepartment of General SurgeryUniversity Hospital Giessen and Marburg, Campus Giessen, Rudolf-Buchheim-Strasse 7, 35385 Giessen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Wichmann
authors.affiliation: Department of General SurgeryEndocrine Center, University Hospital Giessen and Marburg, Campus Marburg, Baldingerstrasse, 35043 Marburg, GermanyDepartment of General SurgeryUniversity Hospital Giessen and Marburg, Campus Giessen, Rudolf-Buchheim-Strasse 7, 35385 Giessen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Baier
authors.affiliation: Department of General SurgeryEndocrine Center, University Hospital Giessen and Marburg, Campus Marburg, Baldingerstrasse, 35043 Marburg, GermanyDepartment of General SurgeryUniversity Hospital Giessen and Marburg, Campus Giessen, Rudolf-Buchheim-Strasse 7, 35385 Giessen, Germany.
authors.forename: J P
authors.initials: JP
authors.lastname: Holler
authors.affiliation: Department of General SurgeryEndocrine Center, University Hospital Giessen and Marburg, Campus Marburg, Baldingerstrasse, 35043 Marburg, GermanyDepartment of General SurgeryUniversity Hospital Giessen and Marburg, Campus Giessen, Rudolf-Buchheim-Strasse 7, 35385 Giessen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ramaswamy
authors.affiliation: Department of General SurgeryEndocrine Center, University Hospital Giessen and Marburg, Campus Marburg, Baldingerstrasse, 35043 Marburg, GermanyDepartment of General SurgeryUniversity Hospital Giessen and Marburg, Campus Giessen, Rudolf-Buchheim-Strasse 7, 35385 Giessen, Germany.
authors.forename: D K
authors.initials: DK
authors.lastname: Bartsch
authors.affiliation: Department of General SurgeryEndocrine Center, University Hospital Giessen and Marburg, Campus Marburg, Baldingerstrasse, 35043 Marburg, GermanyDepartment of General SurgeryUniversity Hospital Giessen and Marburg, Campus Giessen, Rudolf-Buchheim-Strasse 7, 35385 Giessen, Germany jwaldman@med.uni-marburg.de.
authors.forename: J
authors.initials: J
authors.lastname: Waldmann
mesh_terms: D007516:Adenoma, Islet Cell / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004656:Enalapril / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D055815:Young Adult
chemical_list: C544066:Agtr1a protein, mouse; D000806:Angiotensin-Converting Enzyme Inhibitors; D000970:Antineoplastic Agents; D016861:Cyclooxygenase Inhibitors; D016328:NF-kappa B; D044140:Receptor, Angiotensin, Type 1; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D004656:Enalapril; D001241:Aspirin
keywords: ACE inhibitors; Rip1-Tag2 mouse model; aspirin; chemoprevention; neuroendocrine tumors