{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T20:41:06Z","timestamp":1792874466487,"version":"4.5.0"},"reference-count":69,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,4,4]],"date-time":"2024-04-04T00:00:00Z","timestamp":1712188800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009560","name":"University Hospital UKGM","doi-asserted-by":"publisher","award":["11\/2023MR"],"award-info":[{"award-number":["11\/2023MR"]}],"id":[{"id":"10.13039\/501100009560","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009560","name":"University Hospital UKGM","doi-asserted-by":"publisher","award":["AH06-01"],"award-info":[{"award-number":["AH06-01"]}],"id":[{"id":"10.13039\/501100009560","id-type":"DOI","asserted-by":"publisher"}]},{"name":"\u201cDeutsche Krebshilfe\u201d (German Cancer Aid)","award":["11\/2023MR"],"award-info":[{"award-number":["11\/2023MR"]}]},{"name":"\u201cDeutsche Krebshilfe\u201d (German Cancer Aid)","award":["AH06-01"],"award-info":[{"award-number":["AH06-01"]}]},{"name":"German Jos\u00e9 Carreras Leukemia foundation","award":["11\/2023MR"],"award-info":[{"award-number":["11\/2023MR"]}]},{"name":"German Jos\u00e9 Carreras Leukemia foundation","award":["AH06-01"],"award-info":[{"award-number":["AH06-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Adjuvant treatment for Glioblastoma Grade 4 with Temozolomide (TMZ) inevitably fails due to therapeutic resistance, necessitating new approaches. Apoptosis induction in GB cells is inefficient, due to an excess of anti-apoptotic XPO1\/Bcl-2-family proteins. We assessed TMZ, Methotrexate (MTX), and Cytarabine (Ara-C) (apoptosis inducers) combined with XPO1\/Bcl-2\/Mcl-1-inhibitors (apoptosis rescue) in GB cell lines and primary GB stem-like cells (GSCs). Using CellTiter-Glo\u00ae and Caspase-3 activity assays, we generated dose\u2013response curves and analyzed the gene and protein regulation of anti-apoptotic proteins via PCR and Western blots. Optimal drug combinations were examined for their impact on the cell cycle and apoptosis induction via FACS analysis, paralleled by the assessment of potential toxicity in healthy mouse brain slices. Ara-C and MTX proved to be 150- to 10,000-fold more potent in inducing apoptosis than TMZ. In response to inhibitors Eltanexor (XPO1; E), Venetoclax (Bcl-2; V), and A1210477 (Mcl-1; A), genes encoding for the corresponding proteins were upregulated in a compensatory manner. TMZ, MTX, and Ara-C combined with E, V, and A evidenced highly lethal effects when combined. As no significant cell death induction in mouse brain slices was observed, we conclude that this drug combination is effective in vitro and expected to have low side effects in vivo.<\/jats:p>","DOI":"10.3390\/cells13070632","type":"journal-article","created":{"date-parts":[[2024,4,4]],"date-time":"2024-04-04T10:42:03Z","timestamp":1712227323000},"page":"632","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A Novel Approach for Glioblastoma Treatment by Combining Apoptosis Inducers (TMZ, MTX, and Cytarabine) with E.V.A. (Eltanexor, Venetoclax, and A1210477) Inhibiting XPO1, Bcl-2, and Mcl-1"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5186-2952","authenticated-orcid":false,"given":"Kai","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Philipps University Marburg, Baldingerstra\u00dfe 1, 35043 Marburg, Germany"},{"name":"Department of Hematology, Oncology & Immunology, Philipps University Marburg, Baldingerstra\u00dfe 1, 35043 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madita","family":"Braun","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Philipps University Marburg, Baldingerstra\u00dfe 1, 35043 Marburg, Germany"},{"name":"Department of Hematology, Oncology & Immunology, Philipps University Marburg, Baldingerstra\u00dfe 1, 35043 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonie","family":"Meyer","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Philipps University Marburg, Baldingerstra\u00dfe 1, 35043 Marburg, Germany"},{"name":"Department of Hematology, Oncology & Immunology, Philipps University Marburg, Baldingerstra\u00dfe 1, 35043 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Otte","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Philipps University Marburg, Baldingerstra\u00dfe 1, 35043 Marburg, Germany"},{"name":"Department of Hematology, Oncology & Immunology, Philipps University Marburg, Baldingerstra\u00dfe 1, 35043 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hartmann","family":"Raifer","sequence":"additional","affiliation":[{"name":"FACS Core Facility, Philipps University Marburg, Hans-Meerwein-Stra\u00dfe 3, 35043 Marburg, 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Urban","sequence":"additional","affiliation":[{"name":"University Cancer Center (UCT) Frankfurt\u2014Marburg, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany"},{"name":"Dr. Senckenberg Institute of Neurooncology, Goethe-University of Frankfurt, Schleusenweg 2-16, 60528 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1402-6290","authenticated-orcid":false,"given":"Michael W.","family":"Ronellenfitsch","sequence":"additional","affiliation":[{"name":"University Cancer Center (UCT) Frankfurt\u2014Marburg, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany"},{"name":"Dr. Senckenberg Institute of Neurooncology, Goethe-University of Frankfurt, Schleusenweg 2-16, 60528 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim P.","family":"Steinbach","sequence":"additional","affiliation":[{"name":"University Cancer Center (UCT) Frankfurt\u2014Marburg, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany"},{"name":"Dr. Senckenberg Institute of Neurooncology, Goethe-University of Frankfurt, Schleusenweg 2-16, 60528 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelena","family":"Pesek","sequence":"additional","affiliation":[{"name":"Medical Mass Spectrometry Core Facility, Philipps University Marburg, Baldingerstra\u00dfe 1, 35043 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Watzer","sequence":"additional","affiliation":[{"name":"Medical Mass Spectrometry Core Facility, Philipps University Marburg, Baldingerstra\u00dfe 1, 35043 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang A.","family":"Nockher","sequence":"additional","affiliation":[{"name":"Medical Mass 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