361506 20260304232653.0 10.3389/fonc.2025.1633299 doi 10.15120/GSI-2025-00970 datacite_doi 40900796 pmid WOS:001563580900001 WOS GSI-2025-00970 English 610 Kratz, Katja P:(DE-Ds200)OR0642 0 First author gsi 2-Deoxy-D-Glucose and ES-936 sensitize cancer- but not normal cells to both low- and high LET irradiation Lausanne 2025 Frontiers Media article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1772634592_332559 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Metabolic differences of normal- and cancer cells represent an important target for the development of novel cancer treatment strategies. Given that radiotherapy constitutes one of the primary treatment modalities for solid cancers, the targeting of cancer cell metabolism to enhance their sensitivity to irradiation emerges as a promising approach. The utilization of glycolysis even under aerobic conditions in cancer cells presents a unique target to deprive cancer cells of energy and metabolites required not only for their rapid cell growth but also for the repair of irradiation induced DNA damage. Furthermore, cancer cells have been observed to exhibit elevated levels of reactive oxygen species and potentially react more sensitively to an induced disturbance of the redox balance, especially after irradiation mediated oxidative stress. Overall, interference with aerobic glycolysis and the oxidative stress response could potentiate the anti-proliferative and cytotoxic effects of cancer cell irradiation, while sparing normal cells.To analyze the effect of inhibitors targeting the cellular metabolism and redox balance, normal fibroblast- and cancer cell lines were characterized using a Seahorse XFp metabolic analyzer, followed by Sulforhodamin B proliferation assays and flow cytometry based cell cycle analysis. Furthermore, NADP+/NADPH-, NAD(P)H- and ROS levels were determined using bioluminescent assays, Fluorescence Lifetime Imaging Microscopy (FLIM) and fluorescent microscopy. Radiosensitization of cell lines was assessed through clonogenic survival assays and analyses of DNA-repair efficiency via fluorescence microscopy.The present study demonstrates that the glycolytic inhibitor 2-deoxy-D-glucose and the NAD(P)H:quinone oxidoreductase inhibitor ES-936 can render cancer cells more sensitive to X-rays and densely ionizing radiation (high-linear energy transfer (LET) irradiation) like alpha-particles or heavy ions but do not affect normal fibroblasts. While inhibitor-treated and low-LET (X-ray) irradiated cancer cells exhibited a decreased clonal survival, an additional DNA repair defect was observed after high-LET irradiation.Our results imply that distinct mechanisms influence the clonal survival and DNA repair of irradiated, inhibitor-treated cancer cells in dependence of the LET. The findings of this study suggest that the combination of inhibitors targeting glycolysis and the redox balance may represent a promising strategy to enhance the sensitivity of cancer cells to both photon- and charged particle therapy. 633 - Life Sciences – Building Blocks of Life: Structure and Function (POF4-633) G:(DE-HGF)POF4-633 POF4-633 POF IV 0 02NUK054A - Verbundprojekt VERCHROMT II: Erkennung, Verarbeitung und biologische Konsequenzen von Chromatinschäden nach Teilchenbestrahlung II, Teilprojekt A (BMBF-02NUK054A) G:(DE-Ds200)BMBF-02NUK054A BMBF-02NUK054A 1 FAIR Phase-0 - FAIR Phase-0 Research Program (GSI-FAIR-Phase-0) G:(Ds200)GSI-FAIR-Phase-0 GSI-FAIR-Phase-0 2 SUC-GSI-Darmstadt - Strategic university cooperation GSI-TU Darmstadt (SUC-GSI-DA) G:(DE-Ds200)SUC-GSI-DA SUC-GSI-DA 3 Dataset connected to CrossRef, Journals: repository.gsi.de 2-deoxy-D-glucose Other DNA-repair Other cancer Other carbon-ions Other glycolysis Other high-LET Other metabolism Other radiotherapy Other EXP:(DE-Ds200)UBio08_Jakob-20221208 EXP:(DE-Ds200)UBio08_Jakob-20221208 Radiation-Induced DNA Damage Response in Dependency of Cell Metabolism, Chromatin Structure and DNA Repair (Station: X6) 0 Förster, Henrieke P:(DE-Ds200)OR9353 1 gsi Vogel, Kira P:(DE-Ds200)OR13444 2 Durante, Marco P:(DE-Ds200)OR2413 3 gsi Jakob, Burkhard P:(DE-Ds200)OR0522 4 Corresponding author gsi 10.3389/fonc.2025.1633299 Vol. 15, p. 1633299 PERI:(DE-600)2649216-7 1633299 Frontiers in oncology 15 2025 2234-943X http://repository.gsi.de/record/361506/files/fonc-1-1633299.pdf OpenAccess http://repository.gsi.de/record/361506/files/fonc-1-1633299.pdf?subformat=pdfa pdfa OpenAccess oai:repository.gsi.de:361506 openaire open_access OpenAPC driver VDB openCost dnbdelivery GSI Helmholtzzentrum für Schwerionenforschung GmbH I:(DE-Ds200)20121206GSI GSI 0 P:(DE-Ds200)OR0642 GSI Helmholtzzentrum für Schwerionenforschung GmbH I:(DE-Ds200)20121206GSI GSI 1 P:(DE-Ds200)OR9353 GSI Helmholtzzentrum für Schwerionenforschung GmbH I:(DE-Ds200)20121206GSI GSI 3 P:(DE-Ds200)OR2413 GSI Helmholtzzentrum für Schwerionenforschung GmbH I:(DE-Ds200)20121206GSI GSI 4 P:(DE-Ds200)OR0522 DE-HGF Forschungsbereich Materie Von Materie zu Materialien und Leben G:(DE-HGF)POF4-630 G:(DE-HGF)POF4-633 G:(DE-HGF)POF4 G:(DE-HGF)POF4-600 G:(DE-HGF)POF Life Sciences – Building Blocks of Life: Structure and Function 0 2025 APC keys set PC:(DE-HGF)0000 APC Local Funding PC:(DE-HGF)0001 APC DFG OA Publikationskosten PC:(DE-HGF)0002 APC DOAJ Journal PC:(DE-HGF)0003 APC Creative Commons Attribution CC BY 4.0 LIC:(DE-HGF)CCBY4 HGFVOC OpenAccess StatID:(DE-HGF)0510 StatID JCR StatID:(DE-HGF)0100 StatID FRONT ONCOL : 2022 2024-12-18 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2024-12-18 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2024-12-18 DBCoverage StatID:(DE-HGF)0501 StatID DOAJ Seal 2024-08-08T17:01:20Z DBCoverage StatID:(DE-HGF)0500 StatID DOAJ 2024-08-08T17:01:20Z Peer Review StatID:(DE-HGF)0030 StatID DOAJ : Anonymous peer review 2024-08-08T17:01:20Z DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2024-12-18 DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2024-12-18 DBCoverage StatID:(DE-HGF)1110 StatID Current Contents - Clinical Medicine 2024-12-18 WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2024-12-18 DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2024-12-18 IF < 5 StatID:(DE-HGF)9900 StatID 2024-12-18 Article Processing Charges StatID:(DE-HGF)0561 StatID 2024-12-18 Fees StatID:(DE-HGF)0700 StatID 2024-12-18 yes I:(DE-Ds200)BIO-20160831OR354 BIO Biophysik 0 I:(DE-Ds200)Coll-FAIR-BIO BIO@FAIR Collaboration FAIR: BIO 1 journal VDB I:(DE-Ds200)BIO-20160831OR354 I:(DE-Ds200)Coll-FAIR-BIO APC UNRESTRICTED APC FullTexts