{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:53:33Z","timestamp":1760241213917,"version":"build-2065373602"},"reference-count":41,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,12,12]],"date-time":"2019-12-12T00:00:00Z","timestamp":1576108800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["287954"],"award-info":[{"award-number":["287954"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Glioblastoma (GB), a grade IV glioma, with high heterogeneity and chemoresistance, obligates a multidimensional antagonist to debilitate its competence. Considering the previous reports on thioesters as antitumor compounds, this paper investigates on use of this densely functionalized sulphur rich molecule as a potent anti-GB agent. Bio-evaluation of 12 novel compounds, containing \u03b1-thioether ketone and orthothioester functionalities, identified that five analogs exhibited better cytotoxic profile compared to standard drug cisplatin. Detailed toxicity studies of top compound were evaluated in two cell lines, using cell viability test, apoptotic activity, oxidative stress and caspase activation and RNA-sequencing analysis, to obtain a comprehensive molecular profile of drug activity. The most effective molecule presented half maximal inhibitory concentration (IC50) values of 27 \u03bcM and 23 \u03bcM against U87 and LN229 GB cells, respectively. Same compound effectively weakened various angiogenic pathways, mainly MAPK and JAK-STAT pathways, downregulating VEGF. Transcriptome analysis identified significant promotion of apoptotic genes, and genes involved in cell cycle arrest, with concurrent inhibition of various tyrosine kinase cascades and stress response genes. Docking and immunoblotting studies suggest EGFR as a strong target of the orthothioester identified. Therefore, orthothioesters can potentially serve as a multi-dimensional chemotherapeutic possessing strong cytotoxic, anti-angiogenic and chemo-sensitization activity, challenging glioblastoma pathogenesis.<\/jats:p>","DOI":"10.3390\/cells8121624","type":"journal-article","created":{"date-parts":[[2019,12,12]],"date-time":"2019-12-12T11:06:41Z","timestamp":1576148801000},"page":"1624","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Battling Glioblastoma: A Novel Tyrosine Kinase Inhibitor with Multi-Dimensional Anti-Tumor Effect"],"prefix":"10.3390","volume":"8","author":[{"given":"Anisha","family":"Viswanathan","sequence":"first","affiliation":[{"name":"Molecular Signaling Lab, Faculty of Medicine and Health Technology, Tampere University and BioMeditech, P.O. Box 553, 33101 Tampere, Finland"},{"name":"Tays Cancer Center, Tampere University Hospital, 33520 Tampere, Finland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1217-2638","authenticated-orcid":false,"given":"Aliyu","family":"Musa","sequence":"additional","affiliation":[{"name":"Predictive Medicine and Data Analytics Lab, Faculty of Medicine and Health Technology, Tampere University and BioMediTech, P.O. Box 553, 33101 Tampere, Finland"}]},{"given":"Akshaya","family":"Murugesan","sequence":"additional","affiliation":[{"name":"Molecular Signaling Lab, Faculty of Medicine and Health Technology, Tampere University and BioMeditech, P.O. Box 553, 33101 Tampere, Finland"},{"name":"Tays Cancer Center, Tampere University Hospital, 33520 Tampere, Finland"},{"name":"Department of Biotechnology, Lady Doak College, Madurai 625002, India"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0411-9618","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Vale","sequence":"additional","affiliation":[{"name":"Faculty of Engineering and Natural Sciences, Tampere University, 33101 Tampere, Finland"},{"name":"Instituto de Investiga\u00e7\u00e3o do Medicamento (iMed.ULisboa), Faculdade de Farm\u00e1cia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7284-5948","authenticated-orcid":false,"given":"Carlos","family":"Afonso","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o do Medicamento (iMed.ULisboa), Faculdade de Farm\u00e1cia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5541-234X","authenticated-orcid":false,"given":"Saravanan","family":"Konda Mani","sequence":"additional","affiliation":[{"name":"Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China"}]},{"given":"Olli","family":"Yli-Harja","sequence":"additional","affiliation":[{"name":"Computational Systems Biology Group, Faculty of Medicine and Health Technology, Tampere University and BioMediTech, P.O. Box 553, 33101 Tampere, Finland"},{"name":"Institute for Systems Biology, 1441N 34th Street, Seattle, WA 98103-8904, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2414-9064","authenticated-orcid":false,"given":"Nuno","family":"Candeias","sequence":"additional","affiliation":[{"name":"Faculty of Engineering and Natural Sciences, Tampere University, 33101 Tampere, Finland"}]},{"given":"Meenakshisundaram","family":"Kandhavelu","sequence":"additional","affiliation":[{"name":"Molecular Signaling Lab, Faculty of Medicine and Health Technology, Tampere University and BioMeditech, P.O. Box 553, 33101 Tampere, Finland"},{"name":"Tays Cancer Center, Tampere University Hospital, 33520 Tampere, Finland"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/nm0603-669","article-title":"The biology of VEGF and its receptors","volume":"9","author":"Ferrara","year":"2003","journal-title":"Nat. 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