{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:41:44Z","timestamp":1792460504006,"version":"4.5.0"},"reference-count":45,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,20]],"date-time":"2025-07-20T00:00:00Z","timestamp":1752969600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan","award":["24K02553"],"award-info":[{"award-number":["24K02553"]}]},{"name":"Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan","award":["23K06689"],"award-info":[{"award-number":["23K06689"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cellular senescence is a state of the durable cell cycle arrest of dysfunctional cells, which has been associated with the promotion of tumor cell reprogramming into a stem cell state. We previously reported that the mixed lineage kinase (MLK) inhibitor CEP-1347 promotes the differentiation of glioma stem cells (GSCs)\u2014key contributors to glioblastoma recurrence and therapy resistance\u2014into non-stem tumor cells. However, we also noted that CEP-1347\u2013treated GSCs exhibited a morphological change suggestive of senescence. Therefore, we herein investigated whether CEP-1347 induces senescence in GSCs and, consequently, if senescent GSCs may be eliminated using senolytics. Cell death induced by CEP-1347 in combination with senolytic agents or with the knockdown of anti-apoptotic BCL2 family genes, as well as the effects of CEP-1347 on the expression of senescence markers and anti-apoptotic Bcl-2 family proteins, were examined. The results obtained showed that CEP-1347 induced senescence in GSCs accompanied by the increased expression of Bcl-xL. Among the panel of senolytic agents tested, navitoclax, a BH3 mimetic, efficiently induced cell death in GSCs when combined with CEP-1347 at concentrations clinically achievable in the brain. The knockdown of Bcl-xL resulted in more pronounced GSC death in combination with CEP-1347 than that of Bcl-2. These results suggest that combining CEP-1347 with the targeting of Bcl-xL, the expression of which increases with CEP-1347-induced senescence, is a rational approach to ensure the elimination of GSCs, thereby improving the outcomes of glioblastoma treatment.<\/jats:p>","DOI":"10.3390\/ijms26146984","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T09:33:53Z","timestamp":1753090433000},"page":"6984","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Targeting Bcl-xL with Navitoclax Effectively Eliminates Senescent Tumor Cells That Appear Following CEP-1347-Induced Differentiation of Glioma Stem Cells"],"prefix":"10.3390","volume":"26","author":[{"given":"Senri","family":"Takenouchi","sequence":"first","affiliation":[{"name":"Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasufumi","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan"},{"name":"Department of Obstetrics and Gynecology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan"},{"name":"Department of Neurosurgery, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9904-8842","authenticated-orcid":false,"given":"Yurika","family":"Nakagawa-Saito","sequence":"additional","affiliation":[{"name":"Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Mitobe","sequence":"additional","affiliation":[{"name":"Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan"},{"name":"Department of Neurosurgery, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keita","family":"Togashi","sequence":"additional","affiliation":[{"name":"Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan"},{"name":"Department of Ophthalmology and Visual Sciences, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1975-0146","authenticated-orcid":false,"given":"Shuhei","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan"},{"name":"Department of Clinical Oncology, Yamagata Prefectural Shinjo Hospital, 720-1 Kanazawa, Shinjo 996-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asuka","family":"Sugai","sequence":"additional","affiliation":[{"name":"Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7651-1374","authenticated-orcid":false,"given":"Yukihiko","family":"Sonoda","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chifumi","family":"Kitanaka","sequence":"additional","affiliation":[{"name":"Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan"},{"name":"Research Institute for Promotion of Medical Sciences, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6333-6076","authenticated-orcid":false,"given":"Masashi","family":"Okada","sequence":"additional","affiliation":[{"name":"Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1001\/jama.2023.0023","article-title":"Glioblastoma and Other Primary Brain Malignancies in Adults: A Review","volume":"329","author":"Schaff","year":"2023","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/S1470-2045(09)70025-7","article-title":"Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial","volume":"10","author":"Stupp","year":"2009","journal-title":"Lancet Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Eckerdt, F., and Platanias, L.C. 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