Angiotensin-(1–7), a small molecule inhibitor of glioblastoma growth

Abstract

2024 Background: Recent studies suggest that anti-angiogenic therapies may be effective in patients with glioblastoma multiforme (GBM), a highly vascular tumor. We have previously demonstrated that angiotensin-(1–7) [Ang-(1–7)], an endogenous heptapeptide with anti-angiogenic properties, significantly reduced the serum-stimulated growth of three human glioblastoma cell lines which contained mRNA for the AT(1–7) receptor mas. We now provide the first evidence that Ang-(1–7) markedly decreases the proliferation and growth of human glioblastomas in vivo using a xenograft model. Methods: Athymic mice with tumors resulting from injection of human U87 glioblastoma cells were treated for 18 days with saline or 1000 μg/kg Ang-(1–7), delivered by subcutaneous injection every 12 h. Results: The average volume of the tumors from mice treated with the heptapeptide was approximately 3-fold less than the size of the tumors from control animals (586.1 ± 94.5 mm3 vs 1845.5 ± 238.1 mm3; n = 6, p < 0.05). Further, the tumors from mice injected with Ang-(1–7) weighed almost 50% less than the tumors from mice treated with saline (1.31 ± 0.12 g vs. 2.45 ± 0.23 g; n = 6, p < 0.05). The Ang-(1–7)-mediated reduction in tumor growth was associated with a significant decrease in immunoreactive Ki67, a proliferation marker. In addition, a marked down-regulation of cyclooxygenase 2 (COX-2), prostaglandin E synthase (PGES-1) and vascular endothelial growth factor (VEGF) was observed in tumors from Ang-(1–7)-injected mice compared to saline-treated controls (COX-2: 1.00 ± 0.06 vs 0.55 ± 0.07 relative gene expression; PGES-1: 1.03 ± 0.08 vs. 0.40 ± 0.06; VEGF: 1.05 ± 0.07 vs. 0.59 ± 0.09; n = 6, p < 0.05) with no effect on COX-1 or PGI synthase mRNA. Conclusions: These results suggest that Ang-(1–7) may reduce the concentration and ratio of proliferative and anti-proliferative prostaglandins to decrease glioblastoma growth as well as attenuate angiogenesis through a reduction in VEGF. Thus, Ang-(1–7) may be a new, first-in-class small molecule inhibitor for the treatment of glioblastoma, providing combination therapy as a selective COX-2/PGES-1 and angiogenic inhibitor, targeting a specific AT(1–7) receptor mas. No significant financial relationships to disclose.