{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:13:39Z","timestamp":1790313219197,"version":"4.1.0"},"reference-count":33,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2018,12,11]],"date-time":"2018-12-11T00:00:00Z","timestamp":1544486400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004257","name":"Helse Vest","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004257","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004012","name":"Jane ja Aatos Erkon S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004012","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008730","name":"Kreftforeningen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008730","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005416","name":"Norges Forskningsr\u00e5d","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005416","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012655","name":"Qilu Hospital of Shandong University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012655","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007793","name":"Stiftelsen Kristian Gerhard Jebsen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007793","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:p>Glioblastoma multiforme (GBM) has a poor prognosis with an overall survival of 14\u201315 months after surgery, radiation and chemotherapy using temozolomide (TMZ). A major problem is that the tumors acquire resistance to therapy. In an effort to improve the therapeutic efficacy of TMZ, we performed a genome\u2010wide RNA interference (RNAi) synthetic lethality screen to establish a functional gene signature for TMZ sensitivity in human GBM cells. We then queried the Connectivity Map database to search for drugs that would induce corresponding changes in gene expression. By this approach we identified several potential pharmacological sensitizers to TMZ, where the most potent drug was the established antipsychotic agent Thioridazine, which significantly improved TMZ sensitivity while not demonstrating any significant toxicity alone. Mechanistically, we show that the specific chemosensitizing effect of Thioridazine is mediated by impairing autophagy, thereby preventing adaptive metabolic alterations associated with TMZ resistance. Moreover, we demonstrate that Thioridazine inhibits late\u2010stage autophagy by impairing fusion between autophagosomes and lysosomes. Finally, Thioridazine in combination with TMZ significantly inhibits brain tumor growth <jats:italic>in vivo<\/jats:italic>, demonstrating the potential clinical benefits of compounds targeting the autophagy\u2010lysosome pathway. Our study emphasizes the feasibility of exploiting drug repurposing for the design of novel therapeutic strategies for GBM.<\/jats:p>","DOI":"10.1002\/ijc.31912","type":"journal-article","created":{"date-parts":[[2018,10,6]],"date-time":"2018-10-06T10:07:46Z","timestamp":1538820466000},"page":"1735-1745","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":76,"title":["Thioridazine inhibits autophagy and sensitizes glioblastoma cells to temozolomide"],"prefix":"10.1002","volume":"144","author":[{"given":"Tor\u2010Christian","family":"Johannessen","sequence":"first","affiliation":[{"name":"Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine University of Bergen  Bergen Norway"},{"name":"Department of Oncology Haukeland University Hospital  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Mahdi","family":"Hasan\u2010Olive","sequence":"additional","affiliation":[{"name":"Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaiyang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine University of Bergen  Bergen Norway"},{"name":"Department of Oncology Shandong Chest Hospital  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oxana","family":"Denisova","sequence":"additional","affiliation":[{"name":"Turku Centre for Biotechnology University of Turku and \u00c5bo Akademi University  Turku Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amra","family":"Grudic","sequence":"additional","affiliation":[{"name":"Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Abdul","family":"Latif","sequence":"additional","affiliation":[{"name":"Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Halala","family":"Saed","sequence":"additional","affiliation":[{"name":"Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jobin K.","family":"Varughese","sequence":"additional","affiliation":[{"name":"Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gro Vatne","family":"R\u00f8sland","sequence":"additional","affiliation":[{"name":"Department of Biomedicine University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Yang","sequence":"additional","affiliation":[{"name":"Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine University of Bergen  Bergen Norway"},{"name":"Department of Neurosurgery Qilu Hospital of Shandong University  Jinan China"},{"name":"Brain Science Research Institute Shandong University  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terje","family":"Sundstr\u00f8m","sequence":"additional","affiliation":[{"name":"Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine University of Bergen  Bergen Norway"},{"name":"Department of Neurosurgery Haukeland University Hospital  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Nordal","sequence":"additional","affiliation":[{"name":"Department of Dermatology Haukeland University Hospital  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl Johan","family":"Tronstad","sequence":"additional","affiliation":[{"name":"Department of Biomedicine University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine University of Bergen  Bergen Norway"},{"name":"Department of Neurosurgery Qilu Hospital of Shandong University  Jinan China"},{"name":"Brain Science Research Institute Shandong University  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morten","family":"Lund\u2010Johansen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Haukeland University Hospital  Bergen Norway"},{"name":"Department of Clinical Medicine University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Simonsen","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Institute of Basic Medical Sciences  University of Oslo, Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bassam","family":"Janji","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Hemato\u2010Oncology, Department of Oncology Luxembourg Institute of Health (LIH)  Luxembourg City Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jukka","family":"Westermarck","sequence":"additional","affiliation":[{"name":"Turku Centre for Biotechnology University of Turku and \u00c5bo Akademi University  Turku Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf","family":"Bjerkvig","sequence":"additional","affiliation":[{"name":"Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine University of Bergen  Bergen Norway"},{"name":"NorLux Neuro\u2010Oncology Laboratory, Department of Oncology Luxembourg Institute of Health  Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3367-1260","authenticated-orcid":false,"given":"Lars","family":"Prestegarden","sequence":"additional","affiliation":[{"name":"Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine University of Bergen  Bergen Norway"},{"name":"Department of Dermatology Haukeland University Hospital  Bergen Norway"},{"name":"Department of Clinical Medicine University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,12,11]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa043330"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-03-0384"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(07)70384-4"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-14-0157"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14587"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-1392"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2006.06.001"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1789.2010.01197.x"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI28833"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2014.09.001"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.28984"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-3904"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2044"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1132939"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2012.07.017"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-9-465"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/nos301"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0607668103"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-3514"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.3171\/jns.2006.105.1.111"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2014.07.021"},{"key":"e_1_2_7_23_1","unstructured":"RothBD Psychoactive Drug Screening Program (PDSP). PDSP Ki Database 2011. Contract # HHSN\u2010271\u20102008\u201000025\u2010C (NIMH PDSP)."},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.2063"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-11-0047"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI20039"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.2016111"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.2016311"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.110.174573"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1006\/taap.1999.8688"},{"key":"e_1_2_7_31_1","doi-asserted-by":"crossref","first-page":"2210","DOI":"10.1007\/978-1-4614-9105-7","volume-title":"Drug delivery to the brain: physiological concepts, methodologies and approaches","author":"Hammarlund\u2010Udenaes M","year":"2014"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0082481"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0278-5846(02)00317-2"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1118193109"}],"container-title":["International Journal of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fijc.31912","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ijc.31912","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ijc.31912","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ijc.31912","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,9]],"date-time":"2023-09-09T17:52:42Z","timestamp":1694281962000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ijc.31912"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,11]]},"references-count":33,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2019,4]]}},"alternative-id":["10.1002\/ijc.31912"],"URL":"https:\/\/doi.org\/10.1002\/ijc.31912","archive":["Portico"],"relation":{},"ISSN":["0020-7136","1097-0215"],"issn-type":[{"value":"0020-7136","type":"print"},{"value":"1097-0215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,12,11]]},"assertion":[{"value":"2017-09-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-08-30","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-12-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}