Repurposing Amlodipine for Glioblastoma: A Proteomics study with relevance to pharmacy practice

Abstract

Background: Glioblastoma (GBM) is a highly aggressive brain malignancy with limited treatment options due to recurrence, therapy resistance, and invasiveness. Chemotherapy, though essential, is often hindered by severe side effects and chemoresistance. This highlights the need for alternative therapies with reduced cytotoxicity. Recent studies suggest that calcium channel blockers, such as amlodipine, may exhibit anticancer properties across various malignancies. Objectives: This study aimed to investigate the molecular changes induced by amlodipine in U87 and U373 GBM cell lines using quantitative proteomics to assess its potential as a repurposed therapeutic agent. Methods: Quantitative proteomic analysis was performed using UHPLC- ESI-QTOF-MS on U87 and U373 GBM cell lines treated with amlodipine. Statistical analysis was conducted using a Student’s t-test with a q-value < 0.05 to identify significantly dysregulated proteins. Results: A total of 1,820 proteins in U87 and 2,250 proteins in U373 were identified. Statistical analysis revealed 77 significantly dysregulated proteins in U87 and 14 in U373. Functional enrichment analysis demonstrated distinct pathway alterations between the two cell lines following amlodipine treatment. In U87 cells, mitochondrial oxidative phosphorylation pathways were deactivated, including NADH dehydrogenase and mitochondrial respiratory chain complex, with significant downregulation of NDUFS1, NDUFS2, and MT-ND4, proteins essential for energy production. In U373 cells, the fluid shear stress and atherosclerosis pathways were activated, with SQSTM1/p62 significantly upregulated. Notably, SQSTM1 was upregulated in both cell lines (4.7-fold in U87 and 2.9-fold in U373), suggesting a potential link between calcium influx inhibition and GBM stress response mechanisms. Conclusion: This study provides a comprehensive molecular map of amlodipine-induced proteomic alterations in GBM, highlighting its potential as a repurposed therapeutic agent. The distinct pathway alterations observed between U87 and U373 cell lines underscore the complexity of GBM biology and suggest that calcium channel blockers may exert cell-line-specific effects.