Biomarker-Guided Drug Repurposing and Molecular Validation of Angiotensin-2 Receptor Type-1 in Brain Tumor

Abstract

Glioma, the most frequent and malignant brain tumor, is one of the most lethal forms of cancer. Among a wide range of aberrantly expressed genes, Angiotensin-2 Receptor Type-1 (AGTR1) is reported to be up-regulated in glioma and associated with aggressive tumor traits and progression. The current study evaluates the anticancer potential of commonly used angiotensin receptor blocker (ARB) telmisartan. A total of eleven, Food and Drug Administration (FDA) approved ARBs were selected, and eight drugs were docked against the AGTR1 receptor. The antihypertensive drug with the highest docking score was selected for in vitro experimentation. Half maximal inhibitory concentration was determined and subsequently applied to patient-derived glioma cell lines. Quantitative gene expression post-drug treatment was determined through real-time polymerase chain reaction (PCR). In vitro growth inhibitory assays revealed that telmisartan at a dose of 45±0.06 μM was able to inhibit 50% of the cell population in malignant glioma U87 cell lines. The PCR results show that AGTR1 expression in the untreated sample was high, as evidenced by 2^-ΔΔCt values (342.4, 138.5, 1467.3) for sample IK148-Glioblastma multiform (GBM), IK163-low grade glioma (LGG), and IK231-Medulloblastoma (MDB), respectively. The comparison was made with positive control U-87 cell lines. Following the drug treatment, an increase in the cycle threshold (Ct) mean value for AGTR1 was observed, coinciding with a decrease in mean fold changes of 0.06±0.8, 0.5±2.0, and 0.02±0.02 for GBM, LGG, and MDB samples, respectively. Based on the findings of this study, it can be concluded that telmisartan exhibits successful inhibitory effects against AGTR1 expression in glioma cell lines.