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In this work, glucosylceramide synthase (GCS) was targeted, using RNA interference technology (siRNAs), in U87 and DBTRG human glioblastoma (GBM) cells, as in both cell types GCS showed to be overexpressed with respect to normal human astrocytes. The efficacy of a combined therapy to tackle GBM, allying GCS silencing to the new generation chemotherapeutics sunitinib and axitinib, or to the alkylating drugs etoposide and temozolomide, is evaluated here for the first time. With this purpose, studies addressing GBM cell viability and proliferation, cell cycle and apoptosis were performed, which revealed that combination of GCS silencing with axitinib treatment represents a promising therapeutic approach. The reduction of cell viability induced by this combined therapy is proposed to be mediated by excessive production of reactive oxygen species. This work, identifying GCS as a key molecular target to increase GBM susceptibility to a new generation chemotherapeutic, opens windows to the development of innovative strategies to halt GBM recurrence after surgical resection.<\/jats:p>","DOI":"10.1093\/hmg\/ddz152","type":"journal-article","created":{"date-parts":[[2019,9,11]],"date-time":"2019-09-11T15:27:12Z","timestamp":1568215632000},"page":"3664-3679","source":"Crossref","is-referenced-by-count":8,"title":["Glucosylceramide synthase silencing combined with the receptor tyrosine kinase inhibitor axitinib as a new multimodal strategy for glioblastoma"],"prefix":"10.1093","volume":"28","author":[{"given":"Catarina M","family":"Morais","sequence":"first","affiliation":[{"name":"Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal"},{"name":"Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, Coimbra 3000-456, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3814-6289","authenticated-orcid":false,"given":"Pedro P","family":"Cunha","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal"}]},{"given":"T\u00e2nia","family":"Melo","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Centre, Department of Chemistry and QOPNA, University of Aveiro, Aveiro 3810-193, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1629-4782","authenticated-orcid":false,"given":"Ana M","family":"Cardoso","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal"}]},{"given":"Pedro","family":"Domingues","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Centre, Department of Chemistry and QOPNA, University of Aveiro, Aveiro 3810-193, Portugal"}]},{"given":"M Ros\u00e1rio","family":"Domingues","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Centre, Department of Chemistry and QOPNA, University of Aveiro, Aveiro 3810-193, Portugal"}]},{"given":"Maria C","family":"Pedroso de Lima","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7095-5337","authenticated-orcid":false,"given":"Am\u00e1lia S","family":"Jurado","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal"},{"name":"Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, Coimbra 3000-456, Portugal"}]}],"member":"286","published-online":{"date-parts":[[2019,9,13]]},"reference":[{"key":"2019122311003012700_ref1","doi-asserted-by":"crossref","first-page":"v1","DOI":"10.1093\/neuonc\/now207","article-title":"CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2009-2013","volume":"18","author":"Ostrom","year":"2016","journal-title":"Neuro Oncol."},{"key":"2019122311003012700_ref2","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1056\/NEJMoa043330","article-title":"Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma","volume":"352","author":"Stupp","year":"2005","journal-title":"N. 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