{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:26:32Z","timestamp":1791919592612,"version":"4.3.4"},"reference-count":71,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T00:00:00Z","timestamp":1734307200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["70113307"],"award-info":[{"award-number":["70113307"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:p>\n                    Glioblastoma cells rely on connexin 43 (Cx43)\u2010based gap junctions (GJs) for intercellular communication, enabling them to integrate into a widely branched malignant network. Although there are promising prospects for new targeted therapies, the lack of clinically feasible GJ inhibitors has impeded their adoption in clinical practice. In the present study, we investigated tonabersat (TO), a blood\u2013brain\u2010barrier\u2010penetrating drug with GJ\u2010inhibitory properties, in regard to its potential to disassemble intercellular connectivity in glioblastoma networks. Fluorescence\u2010guided measurements of calcein cell\u2010to\u2010cell transfer were used to study functional intercellular connectivity. Specific DNA fragmentation rates of propidium iodide\u2010stained nuclei were measured as a surrogate readout for cell death using flow cytometry. CRISPR\/Cas9\u2010mediated gene editing of Cx43 served as a validation tool of cellular effects related to Cx43 GJ inhibition. 3\u2032 mRNA sequencing was performed for molecular downstream analysis. We found that TO reduced intercellular GJ\u2010mediated cytosolic traffic and yielded a significant reduction of tumor microtube (TM) length. TO\u2010mediated inhibition of cellular tumor networks was accompanied by a synergistic effect for temozolomide\u2010induced cell death. CRISPR\/Cas9\n                    <jats:italic>Cx43<\/jats:italic>\n                    \u2010knockout revealed similar results, indicating that TO\u2010mediated inhibitory effects rely on the inhibition of Cx43\u2010based GJs. Gene set enrichment analyses found that GJ\u2010mediated synergistic cytotoxic effects were linked to a significant upregulation of cell death signaling pathways. In conclusion, TO disrupts TM\u2010based network connectivity via GJ inhibition and renders glioblastoma cells more susceptible to cytotoxic therapy. Given its previous use in clinical trials for migraine therapy, TO might harbor the potential of bridging the idea of a GJ\u2010targeted therapeutic approach from bench to bedside.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.13786","type":"journal-article","created":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T13:19:56Z","timestamp":1734355196000},"page":"878-898","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Tonabersat enhances temozolomide\u2010mediated cytotoxicity in glioblastoma by disrupting intercellular connectivity through connexin 43 inhibition"],"prefix":"10.1002","volume":"19","author":[{"given":"Elena N. 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