ORIGINAL RESEARCH article
Front. Oncol.
Sec. Radiation Oncology
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1633299
This article is part of the Research TopicMetabolism at the Crossroads of DNA Repair, Immune Response, and Tumor Microenvironment in RadiotherapyView all articles
2-Deoxy-D-Glucose and ES-936 sensitize cancer-but not normal cells to both low-and high LET irradiation
Provisionally accepted
- 1Biophysics, GSI Helmholtz Center for Heavy Ion Research, Helmholtz Association of German Research Centres (HZ), Darmstadt, Germany
- 2Department of Biology, Technische Universitat Darmstadt, Darmstadt, Germany
- 3Department of Physics, Technische Universitat Darmstadt, Darmstadt, Germany
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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. The present study demonstrates that the glycolytic inhibitor 2-deoxy-Dglucose 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 photonand charged particle therapy.
Keywords: Radiotherapy, High-LET, Cancer, Metabolism, DNA-repair, Carbon-ions, Glycolysis, 2-deoxy-D-glucose
Received: 22 May 2025; Accepted: 28 Jul 2025.
Copyright: © 2025 Kratz, Förster, Vogel, Durante and Jakob. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Burkhard Jakob, Biophysics, GSI Helmholtz Center for Heavy Ion Research, Helmholtz Association of German Research Centres (HZ), Darmstadt, Germany
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