{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T01:08:52Z","timestamp":1789002532564,"version":"build-2803163510"},"reference-count":49,"publisher":"Wiley","issue":"20","license":[{"start":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T00:00:00Z","timestamp":1729641600000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","award":["2016049889"],"award-info":[{"award-number":["2016049889"]}],"id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background and Aims<\/jats:title><jats:p>Anti\u2010angiogenic therapies prolong patient survival in some malignancies but not glioblastoma. We focused on the relationship between the differentiation of glioma stem like cells (GSCs) into tumor derived endothelial cells (TDECs) and, anti\u2010angiogenic therapy resistance. Especially we aimed to elucidate the mechanisms of drug resistance of TDECs to anti\u2010angiogenic inhibitors and identify novel anti\u2010angiogenic drugs with clinical applications.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The mouse GSCs, 005, were differentiated into TDECs under hypoxic conditions, and TDECs had endothelial cell characteristics independent of the vascular endothelial growth factor (VEGF) pathway. In\u00a0vivo, inhibition of the VEGF pathway had no anti\u2010tumor effect and increased the percentage of TDECs in the 005 mouse model. Novel anti\u2010angiogenic drugs for glioblastoma were evaluated using a tube formation assay and a drug repositioning strategy with existing blood\u2013brain barrier permeable drugs. Drug screening revealed that the antidepressant sertraline inhibited tube formation of TDECs. Sertraline was administered to differentiated TDECs in\u00a0vitro and 005 mouse models in\u00a0vivo to evaluate genetic changes by RNA\u2010Seq and tumor regression effects by immunohistochemistry and MRI. Sertraline reduced Lama4 and Ang2 expressions of TDEC, which play an important role in non\u2010VEGF\u2010mediated angiogenesis in tumors. The combination of a VEGF receptor inhibitor axitinib, and sertraline improved survival and reduced tumor growth in the 005 mouse model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Collectively, our findings showed the diversity of tumor vascular endothelial cells across VEGF and non\u2010VEGF pathways led to anti\u2010angiogenic resistance. The combination of axitinib and sertraline can represent an effective anti\u2010angiogenic therapy for glioblastoma with safe, low cost, and fast availability.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.70288","type":"journal-article","created":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T12:39:59Z","timestamp":1729687199000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["New Anti\u2010Angiogenic Therapy for Glioblastoma With the Anti\u2010Depressant Sertraline"],"prefix":"10.1002","volume":"13","author":[{"given":"Nobushige","family":"Tsuboi","sequence":"first","affiliation":[{"name":"Department of Neurological Surgery Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences  Okayama Japan"},{"name":"Neutron Therapy Research Center Okayama University  Okayama 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