Primary Role for Kinin B1 and B2 Receptors in Glioma Proliferation

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 × 105 cells in 2 μl/2 min) into the right striatum of adult C57/BL6 wild-type, kinin B1 and B2 receptor knockout (KOB1R and KOB2R) and B1 and B2 receptor 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.