title: Primary Role for Kinin B1and B2Receptors in Glioma Proliferation.
abstract: This study investigated the role of kinins and their receptors in malignant brain tumors. As a first approach, GL-261 glioma cells were injected (2 × 105cells in 2 μl/2 min) into the right striatum of adult C57/BL6 wild-type, kinin B1and B2receptor knockout (KOB1R and KOB2R) and B1and B2receptor double knockout mice (KOB1B2R). The animals received the selective B1R (SSR240612) and/or B2R (HOE-140) antagonists by intracerebroventricular (i.c.v.) route at 5, 10, and 15 days. The tumor size quantification, mitotic index, western blot analysis, quantitative autoradiography, immunofluorescence, and confocal microscopy were carried out in brain tumor samples, 20 days after tumor induction. Our results revealed an uncontrolled tumor growing in KOB1R or SSR240612-treated mice, which was blunted by B2R blockade with HOE-140, suggesting a crosstalk between B1R and B2R in tumor growing. Combined treatment with B1R and B2R antagonists normalized the upregulation of tumor B1R and decreased the tumor size and the mitotic index, as was seen in double KOB1B2R. The B1R was detected on astrocytes in the tumor, indicating a close relationship between this receptor and astroglial cells. Noteworthy, an immunohistochemistry analysis of tumor samples from 16 patients with glioma diagnosis revealed a marked B1R immunopositivity in low-grade gliomas or in older glioblastoma individuals. Furthermore, the clinical data revealed a significantly higher immunopositivity for B1R, when compared to a lower B2R immunolabeling. Taken together, our results show that blocking simultaneously both kinin receptors or alternatively stimulating B1R may be of therapeutic value in the treatment of brain glioblastoma growth and malignancy.
authors.affiliation: Programa de Pós-Graduação em Biologia Celular e Molecular, PUCRS, Avenida Ipiranga 6681, Porto Alegre, RS, 90619-900, Brazil.|Instituto de Toxicologia e Farmacologia, PUCRS, Avenida Ipiranga 6681, Porto Alegre, RS, 90619-900, Brazil.
authors.forename: Natália Fontana
authors.initials: NF
authors.lastname: Nicoletti
authors.affiliation: Department of Molecular and Integrative Physiology, Faculty of Medicine, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montreal H3C 3J7, QC, Canada.
authors.forename: Jacques
authors.initials: J
authors.lastname: Sénécal
authors.affiliation: Laboratório de Patologia, PUCRS, Hospital São Lucas, Avenida Ipiranga, 6681, Porto Alegre, RS, 90619-900, Brazil.
authors.forename: Vinicius Duval
authors.initials: VD
authors.lastname: da Silva
authors.affiliation: Serviço de Neurocirurgia, Hospital São José, Irmandade da Santa Casa de Misericórdia de Porto Alegre, Rua Professor Annes Dias 295, Porto Alegre, RS, 90020-090, Brazil.
authors.forename: Marcelo R
authors.initials: MR
authors.lastname: Roxo
authors.affiliation: Serviço de Neurocirurgia, Hospital São José, Irmandade da Santa Casa de Misericórdia de Porto Alegre, Rua Professor Annes Dias 295, Porto Alegre, RS, 90020-090, Brazil.
authors.forename: Nelson Pires
authors.initials: NP
authors.lastname: Ferreira
authors.affiliation: Departamento de Biofísica, Universidade Federal de São Paulo, Avenida Doutor Arnaldo 455, Sao Paulo, SP, 01246-903, Brazil.
authors.forename: Rafael Leite T
authors.initials: RLT
authors.lastname: de Morais
authors.affiliation: Departamento de Biofísica, Universidade Federal de São Paulo, Avenida Doutor Arnaldo 455, Sao Paulo, SP, 01246-903, Brazil.
authors.forename: João Bosco
authors.initials: JB
authors.lastname: Pesquero
authors.affiliation: Programa de Pós-Graduação em Biologia Celular e Molecular, PUCRS, Avenida Ipiranga 6681, Porto Alegre, RS, 90619-900, Brazil.|Instituto de Toxicologia e Farmacologia, PUCRS, Avenida Ipiranga 6681, Porto Alegre, RS, 90619-900, Brazil.|Faculdade de Odontologia, Laboratório de Patologia, PUCRS, Avenida Ipiranga, 6681, Porto Alegre, RS, 90619-900, Brazil.
authors.forename: Maria Martha
authors.initials: MM
authors.lastname: Campos
authors.affiliation: Department of Molecular and Integrative Physiology, Faculty of Medicine, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montreal H3C 3J7, QC, Canada. rejean.couture@umontreal.ca.
authors.forename: Réjean
authors.initials: R
authors.lastname: Couture
authors.affiliation: Programa de Pós-Graduação em Biologia Celular e Molecular, PUCRS, Avenida Ipiranga 6681, Porto Alegre, RS, 90619-900, Brazil. fernanda.morrone@pucrs.br.|Instituto de Toxicologia e Farmacologia, PUCRS, Avenida Ipiranga 6681, Porto Alegre, RS, 90619-900, Brazil. fernanda.morrone@pucrs.br.|Laboratório de Farmacologia Aplicada, Faculdade de Farmácia, Pontifícia Universidade Católica do Rio Grande do Sul, Avenida Ipiranga, 6681, Partenon, Porto Alegre, RS, 90619-900, Brazil. fernanda.morrone@pucrs.br.
authors.forename: Fernanda Bueno
authors.initials: FB
authors.lastname: Morrone
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology; D005910:Glioma / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D043783:Receptor, Bradykinin B1 / Q000235:genetics / Q000378:metabolism*; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C487113:2-((3-(1,3-benzodioxol-5-yl)-3-(((6-methoxy-2-naphthyl)sulfonyl)amino)propanoyl)amino)-3-(4-((2,6-dimethylpiperidinyl)methyl)phenyl)-N-isopropyl-N-methylpropanamide; D004149:Dioxoles; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D013449:Sulfonamides; C065679:icatibant; D001920:Bradykinin
keywords: B1R and B2R; Glioblastoma; Kinins