{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T04:44:04Z","timestamp":1792557844319,"version":"4.5.0"},"reference-count":51,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,7,23]],"date-time":"2020-07-23T00:00:00Z","timestamp":1595462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Tumor hypoxia is known to limit the efficacy of ionizing radiations, a concept called oxygen enhancement ratio (OER). OER depends on physical factors such as pO2 and linear energy transfer (LET). Biological pathways, such as the hypoxia-inducible transcription factors (HIF), might also modulate the influence of LET on OER. Glioblastoma (GB) is resistant to low-LET radiation (X-rays), due in part to the hypoxic environment in this brain tumor. Here, we aim to evaluate in vitro whether high-LET particles, especially carbon ion radiotherapy (CIRT), can overcome the contribution of hypoxia to radioresistance, and whether HIF-dependent genes, such as erythropoietin (EPO), influence GB sensitivity to CIRT. Hypoxia-induced radioresistance was studied in two human GB cells (U251, GL15) exposed to X-rays or to carbon ion beams with various LET (28, 50, 100\u2009keV\/\u00b5m), and in genetically-modified GB cells with downregulated EPO signaling. Cell survival, radiobiological parameters, cell cycle, and ERK activation were assessed under those conditions. The results demonstrate that, although CIRT is more efficient than X-rays in GB cells, hypoxia can limit CIRT efficacy in a cell-type manner that may involve differences in ERK activation. Using high-LET carbon beams, or targeting hypoxia-dependent genes such as EPO might reduce the effects of hypoxia.<\/jats:p>","DOI":"10.3390\/cancers12082019","type":"journal-article","created":{"date-parts":[[2020,7,23]],"date-time":"2020-07-23T11:26:01Z","timestamp":1595503561000},"page":"2019","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Impact of Hypoxia on Carbon Ion Therapy in Glioblastoma Cells: Modulation by LET and Hypoxia-Dependent Genes"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0355-0270","authenticated-orcid":false,"given":"Samuel","family":"Valable","sequence":"first","affiliation":[{"name":"UNICAEN, CNRS, CEA, ISTCT\/CERVOxy group, GIP Cyceron, Normandie Univ, 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aur\u00e9lie N.","family":"G\u00e9rault","sequence":"additional","affiliation":[{"name":"UNICAEN, CNRS, CEA, ISTCT\/CERVOxy group, GIP Cyceron, Normandie Univ, 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ga\u00eblle","family":"Lambert","sequence":"additional","affiliation":[{"name":"UNICAEN, CNRS, CEA, ISTCT\/CERVOxy group, GIP Cyceron, Normandie Univ, 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marine M.","family":"Leblond","sequence":"additional","affiliation":[{"name":"UNICAEN, CNRS, CEA, ISTCT\/CERVOxy group, GIP Cyceron, Normandie Univ, 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cl\u00e9ment","family":"Anfray","sequence":"additional","affiliation":[{"name":"UNICAEN, CNRS, CEA, ISTCT\/CERVOxy group, GIP Cyceron, Normandie Univ, 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00f4me","family":"Toutain","sequence":"additional","affiliation":[{"name":"UNICAEN, CNRS, CEA, ISTCT\/CERVOxy group, GIP Cyceron, Normandie Univ, 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karim","family":"Bordji","sequence":"additional","affiliation":[{"name":"UNICAEN, CNRS, CEA, ISTCT\/CERVOxy group, GIP Cyceron, Normandie Univ, 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwige","family":"Petit","sequence":"additional","affiliation":[{"name":"UNICAEN, CNRS, CEA, ISTCT\/CERVOxy group, GIP Cyceron, Normandie Univ, 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0778-3397","authenticated-orcid":false,"given":"Myriam","family":"Bernaudin","sequence":"additional","affiliation":[{"name":"UNICAEN, CNRS, CEA, ISTCT\/CERVOxy group, GIP Cyceron, Normandie Univ, 14000 Caen, France"}],"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, CNRS, CEA, ISTCT\/CERVOxy group, GIP Cyceron, Normandie Univ, 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"iv1","DOI":"10.1093\/neuonc\/nov189","article-title":"CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008\u20132012","volume":"17","author":"Ostrom","year":"2015","journal-title":"Neuro-Oncology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/S1470-2045(09)70025-7","article-title":"Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial","volume":"10","author":"Stupp","year":"2009","journal-title":"Lancet Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1093\/neuonc\/nos273","article-title":"Standards of care for treatment of recurrent glioblastoma--Are we there yet?","volume":"15","author":"Weller","year":"2013","journal-title":"Neuro Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"117","DOI":"10.3389\/fmed.2019.00117","article-title":"Hypoxia Imaging and Adaptive Radiotherapy: A State-of-the-Art Approach in the Management of Glioma","volume":"6","author":"Lesueur","year":"2019","journal-title":"Front. 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