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  • Crossing the Blood–Brain Barrier Twice: Network Pharmacology and Bioinformatic Insights into Sertraline–Lomustine Synergy in Glioblastoma

  • Elina Khanehzar,1 Fatemeh Shams,2 Amir Sajad Jafari,3,*
    1. Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran / Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
    2. Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran / Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
    3. Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran / Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran


  • Introduction: Glioblastoma (GBM) is the most aggressive primary brain tumor, with survival rarely exceeding 15 months despite multimodal therapy. Its poor prognosis is driven by therapy resistance, intratumoral heterogeneity, and an immunosuppressive microenvironment. Lomustine, a nitrosourea alkylating agent that crosses the blood–brain barrier (BBB), remains an option for recurrent GBM but has limited efficacy due to resistance. Sertraline, a selective serotonin reuptake inhibitor (SSRI), also crosses the BBB and has been implicated in anticancer activity via autophagy inhibition, efflux pump modulation, and mitochondrial disruption. We aimed to explore the potential synergistic molecular mechanisms of combining sertraline with lomustine in GBM using a network pharmacology approach.
  • Methods: Drug-related targets for sertraline and lomustine were retrieved from SwissTargetPrediction. GBM-associated genes were obtained from the Open Targets Platform. Overlapping targets were identified using Venny 2.0. Protein–protein interaction (PPI) networks were generated in STRING (confidence score >0.4) and analyzed in Cytoscape. Network topology was evaluated using degree, betweenness, and closeness centrality to identify hub genes. Functional enrichment analysis (KEGG pathways, Gene Ontology—biological process, molecular function, cellular component) was performed in STRING to highlight key biological pathways.
  • Results: Thirteen overlapping targets were identified between sertraline, lomustine, and GBM. The STRING PPI network (13 nodes, 16 edges) showed moderate connectivity. Cytoscape analysis revealed EGFR and SLC6A3/SLC6A4 as high-degree hubs, while CA9 and PTGS1 demonstrated high closeness centrality, acting as bridging nodes. Other relevant hubs included PIM1, CA12, ACHE, HTR2A, HTR6, ADRA2B, and CHRM1, capturing GBM’s oncogenic signaling, neurotransmission regulation, and hypoxia adaptation. STRING enrichment analysis revealed significant KEGG pathways including serotonergic synapse, calcium signaling pathway, nitrogen metabolism, and neuroactive ligand–receptor interaction, linking neurotransmission with DNA-damage response. GO biological processes were enriched in one-carbon metabolism, response to nitrogen/oxygen compounds, and synaptic regulation, while GO molecular functions highlighted GPCR activity, serotonin receptor activity, amine binding, carbonic anhydrase activity, and neurotransmitter transporter activity. GO cellular components localized targets to synapses, plasma membrane rafts, and presynaptic/post-synaptic membranes, indicating convergence on neuronal communication and hypoxia-driven tumor adaptation.
  • Conclusion: This network pharmacology study suggests that sertraline and lomustine converge on pathways central to DNA damage response, hypoxia tolerance, inflammatory signaling, neurotransmitter regulation, and apoptosis in GBM. Hub analysis identified EGFR as a central oncogenic driver, while carbonic anhydrases (CA9, CA12) and serotonin transporters/receptors (SLC6A3, SLC6A4, HTR2A, HTR6) reflected GBM’s adaptive signaling and sertraline’s neuromodulatory footprint. Importantly, both agents penetrate the BBB, strengthening clinical relevance. Beyond potentiating lomustine-induced DNA lesions, sertraline may reprogram tumor vulnerabilities by disrupting metabolic resilience, efflux-mediated resistance, and hypoxia adaptation, while touching immune-related pathways such as NFκB and cytokine signaling. These findings support repositioning sertraline as a low-cost, CNS-active chemosensitizer for GBM, warranting experimental validation in preclinical models.
  • Keywords: Glioblastoma, Sertraline, Lomustine, Network Pharmacology, Chemosensitizer

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