{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T08:57:19Z","timestamp":1790326639356,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,5,30]],"date-time":"2020-05-30T00:00:00Z","timestamp":1590796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Glioblastoma (GBM) is one of the most lethal types of tumor due to its high recurrence level in spite of aggressive treatment regimens involving surgery, radiotherapy and chemotherapy. Hypoxia is a feature of GBM, involved in radioresistance, and is known to be at the origin of treatment failure. The aim of this work was to assess the therapeutic potential of a new targeted c-SRC inhibitor molecule, named Si306, in combination with X-rays on the human glioblastoma cell lines, comparing normoxia and hypoxia conditions. For this purpose, the dose modifying factor and oxygen enhancement ratio were calculated to evaluate the Si306 radiosensitizing effect. DNA damage and the repair capability were also studied from the kinetic of \u03b3-H2AX immunodetection. Furthermore, motility processes being supposed to be triggered by hypoxia and irradiation, the role of c-SRC inhibition was also analyzed to evaluate the migration blockage by wound healing assay. Our results showed that inhibition of the c-SRC protein enhances the radiotherapy efficacy both in normoxic and hypoxic conditions. These data open new opportunities for GBM treatment combining radiotherapy with molecularly targeted drugs to overcome radioresistance.<\/jats:p>","DOI":"10.3390\/ijms21113917","type":"journal-article","created":{"date-parts":[[2020,6,2]],"date-time":"2020-06-02T04:09:03Z","timestamp":1591070943000},"page":"3917","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["SRC Tyrosine Kinase Inhibitor and X-rays Combined Effect on Glioblastoma Cell Lines"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5820-9160","authenticated-orcid":false,"given":"Filippo","family":"Torrisi","sequence":"first","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences (BIOMETEC), University of Catania, 95123 Catania, Italy"},{"name":"National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3112-4519","authenticated-orcid":false,"given":"Luigi","family":"Minafra","sequence":"additional","affiliation":[{"name":"National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, 95123 Catania, Italy"},{"name":"Institute of Molecular Bioimaging and Physiology, National Research Council, IBFM-CNR, 90015 Cefal\u00f9, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0554-6649","authenticated-orcid":false,"given":"Francesco P.","family":"Cammarata","sequence":"additional","affiliation":[{"name":"National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, 95123 Catania, Italy"},{"name":"Institute of Molecular Bioimaging and Physiology, National Research Council, IBFM-CNR, 90015 Cefal\u00f9, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano","family":"Savoca","sequence":"additional","affiliation":[{"name":"National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, 95123 Catania, Italy"},{"name":"Institute of Molecular Bioimaging and Physiology, National Research Council, IBFM-CNR, 90015 Cefal\u00f9, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2387-8273","authenticated-orcid":false,"given":"Marco","family":"Calvaruso","sequence":"additional","affiliation":[{"name":"National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, 95123 Catania, Italy"},{"name":"Institute of Molecular Bioimaging and Physiology, National Research Council, IBFM-CNR, 90015 Cefal\u00f9, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5934-3962","authenticated-orcid":false,"given":"Nunzio","family":"Vicario","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences (BIOMETEC), University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Maccari","sequence":"additional","affiliation":[{"name":"Lead Discovery Siena s.r.l. (LDS), via Vittorio Alfieri, 31, Castelnuovo Berardenga, 53019 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6687-1939","authenticated-orcid":false,"given":"Elodie A.","family":"P\u00e9r\u00e8s","sequence":"additional","affiliation":[{"name":"UNICAEN, CEA, CNRS, ISTCT\/CERVOxy Group, GIP Cyceron, Normandie University, 14074 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayriye","family":"\u00d6z\u00e7elik","sequence":"additional","affiliation":[{"name":"UNICAEN, CEA, CNRS, ISTCT\/CERVOxy Group, GIP Cyceron, Normandie University, 14074 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"Bernaudin","sequence":"additional","affiliation":[{"name":"UNICAEN, CEA, CNRS, ISTCT\/CERVOxy Group, GIP Cyceron, Normandie University, 14074 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Botta","sequence":"additional","affiliation":[{"name":"Lead Discovery Siena s.r.l. (LDS), via Vittorio Alfieri, 31, Castelnuovo Berardenga, 53019 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1493-1087","authenticated-orcid":false,"given":"Giorgio","family":"Russo","sequence":"additional","affiliation":[{"name":"National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, 95123 Catania, Italy"},{"name":"Institute of Molecular Bioimaging and Physiology, National Research Council, IBFM-CNR, 90015 Cefal\u00f9, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1614-4696","authenticated-orcid":false,"given":"Rosalba","family":"Parenti","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences (BIOMETEC), University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0355-0270","authenticated-orcid":false,"given":"Samuel","family":"Valable","sequence":"additional","affiliation":[{"name":"UNICAEN, CEA, CNRS, ISTCT\/CERVOxy Group, GIP Cyceron, Normandie University, 14074 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Wen, P.Y., Weller, M., Lee, E.Q., Alexander, B.A., Barnholtz-Sloan, J.S., Barthel, F.P., Batchelor, T.T., Bindra, R.S., Chang, S.M., and Chiocca, E.A. (2020). Glioblastoma in Adults: A Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) Consensus Review on Current Management and Future Directions. Neuro-Oncology.","DOI":"10.1093\/neuonc\/noaa106"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.prro.2016.03.007","article-title":"Radiation therapy for glioblastoma: Executive summary of an American Society for Radiation Oncology Evidence-Based Clinical Practice Guideline","volume":"6","author":"Cabrera","year":"2016","journal-title":"Pract. Radiat. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5079","DOI":"10.1158\/1078-0432.CCR-15-2529","article-title":"ACRIN 6684: Assessment of Tumor Hypoxia in Newly Diagnosed Glioblastoma Using 18F-FMISO PET and MRI","volume":"22","author":"Gerstner","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1667\/RR13959.1","article-title":"Cellular and molecular mechanisms underlying oxygen-dependent radiosensitivity","volume":"183","author":"Liu","year":"2015","journal-title":"Radiat. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"045209","DOI":"10.1088\/2057-1976\/1\/4\/045209","article-title":"A mechanistic investigation of the oxygen fixation hypothesis and oxygen enhancement ratio","volume":"1","author":"Grimes","year":"2015","journal-title":"Biomed. Phys. Eng. Express"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2584","DOI":"10.1177\/0271678X16671965","article-title":"Imaging of brain oxygenation with magnetic resonance imaging: A validation with positron emission tomography in the healthy and tumoural brain","volume":"37","author":"Valable","year":"2017","journal-title":"J. Cereb Blood Flow Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.2967\/jnumed.116.188557","article-title":"In Vivo Relationship Between Hypoxia and Angiogenesis in Human Glioblastoma: A Multimodal Imaging Study","volume":"58","author":"Ponte","year":"2017","journal-title":"J. Nucl. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1100\/2011\/736480","article-title":"The three-layer concentric model of glioblastoma: Cancer stem cells, microenvironmental regulation, and therapeutic implications","volume":"11","author":"Persano","year":"2011","journal-title":"Sci. World J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2101","DOI":"10.18632\/oncotarget.2937","article-title":"Silencing erythropoietin receptor on glioma cells reinforces efficacy of temozolomide and X-rays through senescence and mitotic catastrophe","volume":"6","author":"Peres","year":"2015","journal-title":"Oncotarget"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.canlet.2010.08.014","article-title":"Targeting SRC in glioblastoma tumors and brain metastases: Rationale and preclinical studies","volume":"298","author":"Ahluwalia","year":"2010","journal-title":"Cancer Lett."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Keller, S., and Schmidt, M.H.H. (2017). EGFR and EGFRvIII Promote Angiogenesis and Cell Invasion in Glioblastoma: Combination Therapies for an Effective Treatment. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18061295"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4680","DOI":"10.18632\/oncotarget.6730","article-title":"EGFRvIII\/integrin beta3 interaction in hypoxic and vitronectinenriching microenvironment promote GBM progression and metastasis","volume":"7","author":"Liu","year":"2016","journal-title":"Oncotarget"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7189","DOI":"10.1021\/cr400270z","article-title":"Biologically driven synthesis of pyrazolo[3,4-d]pyrimidines as protein kinase inhibitors: An old scaffold as a new tool for medicinal chemistry and chemical biology studies","volume":"114","author":"Schenone","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1158\/1535-7163.MCT-15-1011","article-title":"Suppression of SRC Signaling Is Effective in Reducing Synergy between Glioblastoma and Stromal Cells","volume":"15","author":"Calgani","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1007\/s00285-008-0222-y","article-title":"Linear quadratic and tumour control probability modelling in external beam radiotherapy","volume":"58","author":"McAneney","year":"2009","journal-title":"J. Math. Biol."},{"key":"ref_16","first-page":"891","article-title":"Effects of mir-128a on the invasion and proliferation of glioma U251 cells","volume":"17","author":"Hu","year":"2019","journal-title":"Oncol. Lett."},{"key":"ref_17","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. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Pirtoli, L., Gravina, G., and Giordano, A. (2016). The \u201cRadioresistance\u201d of Glioblastoma in the Clinical Setting, and the Present Therapeutic Options. Radiobiology of Glioblastoma, Springer.","DOI":"10.1007\/978-3-319-28305-0"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/375577a0","article-title":"Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation","volume":"375","author":"Mukhopadhyay","year":"1995","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Valle-Casuso, J.C., Gonzalez-Sanchez, A., Medina, J.M., and Tabernero, A. (2012). Hif-1 and C-Src Mediate Increased Glucose Uptake Induced by Endothelin-1 and Connexin43 In Astrocytes. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0032448"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Cammarata, F.P., Torrisi, F., Forte, G.I., Minafra, L., Bravata, V., Pisciotta, P., Savoca, G., Calvaruso, M., Petringa, G., and Cirrone, G.A.P. (2019). Proton Therapy and Src Family Kinase Inhibitor Combined Treatments on U87 Human Glioblastoma Multiforme Cell Line. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20194745"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3857\/roj.2012.30.1.1","article-title":"Basics of Particle Therapy Ii: Relative Biological Effectiveness","volume":"30","author":"Choi","year":"2012","journal-title":"Radiat. Oncol. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.stem.2015.02.015","article-title":"The Cancer Stem Cell Niche: How Essential Is The Niche in Regulating Stemness of Tumor Cells?","volume":"16","author":"Plaks","year":"2015","journal-title":"Cell Stem Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3308","DOI":"10.1158\/0008-5472.CAN-08-2158","article-title":"Alphavbeta3\/Alphavbeta5 Integrins-Fak-Rhob: A Novel Pathway for Hypoxia Regulation in Glioblastoma","volume":"69","author":"Skuli","year":"2009","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"8511","DOI":"10.1158\/0008-5472.CAN-05-4340","article-title":"Ionizing Radiation Enhances Matrix Metalloproteinase-2 Secretion and Invasion of Glioma Cells Through Src\/Epidermal Growth Factor Receptor-Mediated P38\/Akt And Phosphatidylinositol 3-Kinase\/Akt Signaling Pathways","volume":"66","author":"Park","year":"2006","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"120","DOI":"10.3389\/fonc.2017.00120","article-title":"Molecular and Microenvironmental Determinants of Glioma Stem-Like Cell Survival and Invasion","volume":"7","author":"Roos","year":"2017","journal-title":"Front. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/nrc1367","article-title":"Exploiting Tumour Hypoxia in Cancer Treatment","volume":"4","author":"Brown","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"687","DOI":"10.4143\/crt.2014.320","article-title":"The Effect of Chemoradiotherapy with SRC Tyrosine Kinase Inhibitor, PP2 and Temozolomide on Malignant Glioma Cells In Vitro and In Vivo","volume":"48","author":"Eom","year":"2016","journal-title":"Cancer Res. Treat."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1021\/jm050603r","article-title":"Pyrazolo[3,4-D]Pyrimidines as Potent Antiproliferative and Proapoptotic Agents Toward A431 And 8701-Bc Cells in Culture Via Inhibition Of C-Src Phosphorylation","volume":"49","author":"Carraro","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1021\/jm5013159","article-title":"Combining X-Ray Crystallography and Molecular Modeling Toward the Optimization of Pyrazolo[3,4-D]Pyrimidines as Potent C-Src Inhibitors Active in Vivo Against Neuroblastoma","volume":"58","author":"Tintori","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1093\/neuonc\/nov011","article-title":"Phase 2 Trial of Dasatinib in Target-Selected Patients With Recurrent Glioblastoma (Rtog 0627)","volume":"17","author":"Lassman","year":"2015","journal-title":"Neuro-Oncology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3790","DOI":"10.1002\/cncr.32340","article-title":"A phase 1 and randomized, placebo-controlled phase 2 trial of bevacizumab plus dasatinib in patients with recurrent glioblastoma: Alliance\/North Central Cancer Treatment Group N0872","volume":"125","author":"Galanis","year":"2019","journal-title":"Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1007\/s11060-012-0848-x","article-title":"Phase 1 trial of dasatinib plus erlotinib in adults with recurrent malignant glioma","volume":"108","author":"Reardon","year":"2012","journal-title":"J. Neuro-Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1093\/neuonc\/nos256","article-title":"EORTC 26083 phase I\/II trial of dasatinib in combination with CCNU in patients with recurrent glioblastoma","volume":"14","author":"Franceschi","year":"2012","journal-title":"Neuro-Oncology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1200\/jco.2015.33.15_suppl.2013","article-title":"Randomized, placebo-controlled, phase II study of dasatinib with standard chemo-radiotherapy for newly diagnosed glioblastoma (GBM), NCCTG N0877 (Alliance)","volume":"33","author":"Laack","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.1158\/1535-7163.MCT-12-0552","article-title":"Active efflux of Dasatinib from the brain limits efficacy against murine glioblastoma: Broad implications for the clinical use of molecularly targeted agents","volume":"11","author":"Agarwal","year":"2012","journal-title":"Mol. Cancer Ther."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Fallacara, A.L., Zamperini, C., Podolski-Renic, A., Dinic, J., Stankovic, T., Stepanovic, M., Mancini, A., Rango, E., Iovenitti, G., and Molinari, A. (2019). A New Strategy for Glioblastoma Treatment: In Vitro and In Vivo Preclinical Characterization of Si306, a Pyrazolo[3,4-d]Pyrimidine Dual Src\/P-Glycoprotein Inhibitor. Cancers, 11.","DOI":"10.3390\/cancers11060848"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1093\/jrr\/rrt111","article-title":"Can the Two Mechanisms of Tumor Cell Killing by Radiation Be Exploited for Therapeutic Gain?","volume":"55","author":"Chapman","year":"2014","journal-title":"J. Radiat. Res."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Joiner, M., and van der Kogel, A. (2009). Basic Clinical Radiobiology, Taylor & Fransis Group. [4th ed.].","DOI":"10.1201\/b15450"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Vicario, N., Bernstock, J.D., Spitale, F.M., Giallongo, C., Giunta, M.A.S., Li Volti, G., Gulisano, M., Leanza, G., Tibullo, D., and Parenti, R. (2019). Clobetasol Modulates Adult Neural Stem Cell Growth via Canonical Hedgehog Pathway Activation. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20081991"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1039\/C7BM01056G","article-title":"Evaluation of RGD functionalization in hybrid hydrogels as 3D neural stem cell culture systems","volume":"6","author":"Mauri","year":"2018","journal-title":"Biomater. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Gulino, R., Vicario, N., Giunta, M.A.S., Spoto, G., Calabrese, G., Vecchio, M., Gulisano, M., Leanza, G., and Parenti, R. (2019). Neuromuscular Plasticity in a Mouse Neurotoxic Model of Spinal Motoneuronal Loss. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20061500"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/11\/3917\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:34:03Z","timestamp":1760175243000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/11\/3917"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,30]]},"references-count":42,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["ijms21113917"],"URL":"https:\/\/doi.org\/10.3390\/ijms21113917","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,30]]}}}