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Metabolic oxidation/reduction reactions and cellular responses to ionizing radiation: A unifying concept in stress response biology
Abstract
Exposure of eukaryotic cells to ionizing radiation (IR) results in the immediate formation of free radicals that last a matter of milliseconds. It has been assumed that the subsequent alterations in multiple intracellular processes following irradiation is due to the initial oxidative damage caused by these free radicals. However, it is becoming increasingly clear that intracellular metabolic oxidation/reduction (redox) reactions can be affected by this initial IR-induced free radical insult and may remain perturbed for minutes, hours, or days. It would seem logical that these cellular redox reactions might contribute to the activation of protective or damaging processes that could impact upon the damaging effects of IR. These processes include redox sensitive signaling pathways, transcription factor activation, gene expression, and metabolic activities that govern the formation of intracellular oxidants and reductants. The physiological manifestations of these radiation-induced alterations in redox sensitive processes have been suggested to contribute to adaptive responses, bystander effects, cell cycle perturbations, cytotoxicity, heat-induced radiosensitization, genomic instability, inflammation, and fibrosis. While a great deal is known about the molecular changes associated with the initial production of free radicals at the time of irradiation, the contribution of perturbations in redox sensitive metabolic processes to biological outcomes following exposure to IR is only recently becoming established. This review will focus on evidence supporting the concept that perturbations in intracellular metabolic oxidation/reduction reactions contribute to the biological effects of radiation exposure as well as new concepts emerging from the field of free radical biology that may be relevant to future studies in radiobiology.
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“The generation of ROS is also an important mediator of the cellular alterations caused by radiation exposure (Diehn et al., 2009; Sonis, 2009; Spitz et al., 2004), including mucositis (Citrin et al., 2010; Cotrim et al., 2007; Cotrim et al., 2005).”
From mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis (2012) · cites this paper as Spitz et al., 2004
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“Low levels of oxidative stress and inflammatory effects are beneficial for body homeostasis, while high levels may initiate a series of biochemical and molecular signaling events; those are detrimental to cell survival (Spitz et al. 2004).”
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“Overall, these results led to the hypothesis that the late ROS accumulation due to changes in cellular metabolism could be an additional mechanism regulating cellular responses to IR exposures.(15) The first report of SOD2 activity being different in transformed cells compared to their corresponding normal cells dates…”
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“Exposure of cells to ionising radiation results in either the direct deposition of energy or the formation of free radicals and reactive oxygen species generated from the radiolysis of water (Spitz et al. 2004).”
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“High-energy X-ray directly generates ROS, which leads to damage of DNA, lipids, proteins, cells, and tissues [32].”
BackgroundLiu, Y., Sun, Y., Li, Y., Bai, H., Xue, F., Xu, S., Xu, H. M., Shi, L., Yang, N., & Chen, J. (2017) · Scientific Reports · doi:10.1038/s41598-017-08738-9 · Cited by 54
Ellagic and ferulic acids alleviate gamma radiation and aluminium chloride-induced oxidative damage
Salem, A. M. H., Mohammaden, T. F., Ali, M. A. M., Mohamed, E. A. K., & Hasan, H. F. (2016) · Life Sciences · doi:10.1016/j.lfs.2016.07.006 · Cited by 54
Lindström, A., Midtbö, K., Arnesson, L.-G., Garvin, S., & Shabo, I. (2017) · Oncotarget · doi:10.18632/oncotarget.17986 · Cited by 57
“Ionizing radiation generates ROS, which are reactive with several cellular macromolecules, including DNA, and promote genomic instability by causing accumulation of mutations [62].”
BackgroundMapuskar, K. A., Anderson, C. M., Spitz, D. R., Batinic̈‐Haberle, I., Allen, B. G., & Oberley‐Deegan, R. E. (2018) · Seminars in Radiation Oncology · doi:10.1016/j.semradonc.2018.10.005 · Cited by 53
Oxidative stress in operating room personnel: occupational exposure to anesthetic gases
Malekırad, A. A., Ranjbar, A., Rahzani, K., Kadkhodaee, M., Rezaie, A. R., ., B. T. B., & Abdollahi, M. R. (2005) · Human & Experimental Toxicology · doi:10.1191/0960327105ht565oa · Cited by 53
Sishc, B. J., Ding, L., Nam, T.-K., Heer, C. D., Rodman, S. N., Schoenfeld, J. D., Fath, M. A., Saha, D., Pulliam, C. F., Langen, B., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abb3768 · Cited by 51
“The third wave of oxidant generation appears to involve both inflammatory responses and mitochondrial electron transport chain processes leading to increased O2 beginning in the days after exposure (22, 25).”
BackgroundInfrared microspectroscopy study of γ-irradiated and H2O2-treated human cells
Gault, N., Rigaud, O., Poncy, J., & Lefaix, J.-L. (2005) · International Journal of Radiation Biology · doi:10.1080/09553000500515368 · Cited by 52
“…dependent on ROS concentration, greater decreases in the absorbance of these bands suggested either a prolonged oxidative stress (Riley 1994, Tulard et al. 2003, Spitz et al. 2004) or a decrease in damaged protein elimination due to a reduced protea- some turnover (Davies 2000, Lasch et al. 2001).”
BackgroundAstragalus polysaccharide ameliorates ionizing radiation-induced oxidative stress in mice
Liu, Y., Liu, F., Yang, Y. P., Li, D., Lv, J., Ou, Y., Sun, F., Chen, J., Shi, Y. H., & Xia, P. (2014) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2014.05.001 · Cited by 52
Jain, M. R., Li, M., Chen, W., Liu, T., de Toledo, S. M., Pandey, B. N., Li, H., Rabin, B. M., & Azzam, E. I. (2011) · Current Molecular Pharmacology · doi:10.2174/1874467211104020106 · Cited by 52
“Thus, though a burst of excess ROS is initially produced at the time of irradiation and is believed to persist for only microseconds or less [72], radiation-induced oxidative stress on the cell may be prolonged due to persistent long-term effects on mitochondrial functions, primarily oxidative metabolism [70], which i…”
BackgroundInfluentialOwens, K. M., Aykin‐Burns, N., Dayal, D., Coleman, M. C., Domann, F. E., & Spitz, D. R. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.10.435 · Cited by 52
“Mutations in genes coding for mitochondrial electron transport chain (ETC) proteins are hypothesized to lead to dysfunctional mitochondrial metabolism resulting in increased steady-state levels of O2 and H2O2, that contribute to genetic instability and carcinogenesis [30].”
BackgroundThe effect on radioresistance of manganese superoxide dismutase in nasopharyngeal carcinoma
Zhao (2010) · Oncology Reports · doi:10.3892/or_00000726 · Cited by 52
Molecular Pathogenesis of Radiation-Induced Cell Toxicity in Stem Cells
Hur, W., & Yoon, S. K. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18122749 · Cited by 54
“This effect enhances apoptosis and cell cycle arrest, subsequently leading to DNA DSBs or DNA SSBs in tumor cell [12], which is termed the “indirect effect” (Figure 1).”
BackgroundWild-Type IDH Enzymes as Actionable Targets for Cancer Therapy
Bergaggio, E., & Piva, R. (2019) · Cancers · doi:10.3390/cancers11040563 · Cited by 52
“It is known that several biomolecules, such as GSH and thioredoxin, require NADPH to mitigate the oxidative stress induced by ionizing radiation [94].”
BackgroundZhu, Y., Mapuskar, K. A., Marek, R. F., Xu, W., Lehmler, H., Robertson, L. W., Hornbuckle, K. C., Spitz, D. R., & Aykin‐Burns, N. (2013) · Toxicological Sciences · doi:10.1093/toxsci/kft186 · Cited by 51
Laiakis, E. C., Hyduke, D. R., & Fornace, A. J. (2012) · Radiation Research · doi:10.1667/rr2771.1 · Cited by 52
“Although rapid induction of ROS is also attributed to LPS treatment and not only to radiation, LPS-generated ROS tend to subside and give rise to nitric oxide at later times (52), whereas radiation-generated ROS and subsequent oxidative stress are persistent (53).”
BackgroundOlsson, M. G., Nilsson, E. J. C., Rutardóttir, S., Paczesny, J., Pallon, J., & Åkerström, B. (2010) · Radiation Research · doi:10.1667/rr2213.1 · Cited by 51
Temme, J., & Bauer, G. (2013) · Radiation Research · doi:10.1667/rr3161.2 · Cited by 51
de Brito, T. V., Neto, J. P. R. P., Prudêncio, R. S., Batista, J. A., Júnior, J. S. C., Silva, R. O., Franco, Á. X., Aragão, K. S., Soares, P. M. G., de Souza, M. H. L. P., et al. (2014) · Journal of Pharmacy and Pharmacology · doi:10.1111/jphp.12231 · Cited by 51
“Concentrations of endogenous antioxidants, such as GSH, are decreased significantly in patients with inflammatory bowel disease and in experimental models of colitis.([49,50]) According this result, we can infer that PLS decreased the mucosa damage acting in the production and action of endogenous antioxidants.”
BackgroundBurdak‐Rothkamm, S., & Rothkamm, K. (2018) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2018.08.001 · Cited by 54
The Cosmic Silence experiment: on the putative adaptive role of environmental ionizing radiation
Carbone, M. C., Pinto, M., Antonelli, F., Amicarelli, F., Balata, M., Belli, M., Devirgiliis, L. C., Ioannucci, L., Nisi, S. D., Sapora, O., et al. (2009) · Radiation and Environmental Biophysics · doi:10.1007/s00411-008-0208-6 · Cited by 50
“It is well known that ionizing radiation induces the production of reactive oxygen species (ROS) in a variety of cells (Spitz et al. 2004), and that such species may be key”
BackgroundKalen, A. L., Sarsour, E. H., Venkataraman, S., & Goswami, P. C. (2006) · Antioxidants and Redox Signaling · doi:10.1089/ars.2006.8.1273 · Cited by 50
“Fold change was calculated as the ratio of peak height for the irradiated cells to that of the corresponding unir-radiated unir-radiated cells.”
Ahmad, I. M., Abdalla, M. Y., Moore, T. A., Bartenhagen, L., Case, A. J., & Zimmerman, M. C. (2019) · Antioxidants · doi:10.3390/antiox8010012 · Cited by 50
“Further, it has been shown that chronic oxidative stress contributes to many pathological conditions including inflammation, fibrosis, and necrosis [8], as well as DNA damage and cancer [9–11].”
BackgroundMolecular hydrogen: A potential radioprotective agent
Hu, Q., Zhou, Y., Wu, S., Wu, W., Deng, Y., & Shao, A. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110589 · Cited by 50
Shukry, M., El‐Shehawi, A. M., El-Kholy, W. M., Elsisy, R. A., Hamoda, H. S., Tohamy, H. G., Abumandour, M. M. A., & Farrag, F. A. (2020) · Animals · doi:10.3390/ani10111996 · Cited by 50
“Additionally, the high level of MDA caused by the LPO effect of MSG may lead to hepatic necrosis [68].”
BackgroundFLASH: New intersection of physics, chemistry, biology, and cancer medicine
Vozenin, M., Loo, B. W., Tantawi, S. G., Maxim, P. G., Spitz, D. R., Bailat, C. J., & Limoli, C. L. (2024) · Reviews of Modern Physics · doi:10.1103/revmodphys.96.035002 · Cited by 59
Feinendegen, L. E., Brooks, A. L., & Morgan, W. F. (2011) · Health Physics · doi:10.1097/hp.0b013e31820a83ae · Cited by 49
Resveratrol Attenuates Radiation Damage in Caenorhabditis elegans by Preventing Oxidative Stress
Ye, K., Ji, C., Lu, X., Ni, Y., Gao, C., Xiao-Hui, C. H. E. N., Zhao, Y., Gu, G., & Guo, X. (2010) · Journal of Radiation Research · doi:10.1269/jrr.10009 · Cited by 50
Ahmad, I. M., Temme, J. B., Abdalla, M. Y., & Zimmerman, M. C. (2016) · Redox Report · doi:10.1080/13510002.2015.1101891 · Cited by 49
Heer, C. D., Davis, A. B., Riffe, D., Wagner, B. A., Falls, K. C., Allen, B. G., Buettner, G. R., Beardsley, R., Riley, D. P., & Spitz, D. R. (2018) · Antioxidants · doi:10.3390/antiox7010018 · Cited by 48
“, NCT02508389) a l receive ra iatio treatment; 2 2 w t m res s t radiation [5,31].”
BackgroundWakayama, S., Ito, D., Kamada, Y., Shimazu, T., Suzuki, T., Nagamatsu, A., Araki, R., Ishikawa, T., Kamimura, S., Hirose, N., et al. (2021) · Science Advances · doi:10.1126/sciadv.abg5554 · Cited by 48
“It is known that radiation induces DNA damage directly or indirectly through radicals generated in response to intracellular water molecules (40, 41).”
BackgroundQuercetin liposomes protect against radiation-induced pulmonary injury in a murine model
Liu, H., XUE, J.-X., Li, X., Ao, R., & Lü, Y. (2013) · Oncology Letters · doi:10.3892/ol.2013.1365 · Cited by 48
“Oxidative stress also contributes to the biological effects of ionizing radiation long after exposure (20).”
Xiong, W., Zhao, J., Yu, H., Li, X., Sun, S., Li, Y., Xia, Q., Zhang, C., He, Q., Gao, X., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0111911 · Cited by 50
“Mitochondria damage by IR can even lead to prolonged oxidative stress and thus further damages DNA and other cellular molecules [4].”
BackgroundModified Citrus Pectin as a Potential Sensitizer for Radiotherapy in Prostate Cancer
Conti, S., Vexler, A. M., Hagoel, L., Kalich‐Philosoph, L., Corn, B. W., Honig, N., Shtraus, N., Meir, Y., Ron, I. G., Eliaz, I., et al. (2018) · Integrative Cancer Therapies · doi:10.1177/1534735418790382 · Cited by 47
“prostate cancer, modified citrus pectin, ionizing radiation, radiosensitivity, galectin-3 Submitted February 18, 2018; revised June 7, 2018; accepted June 28, 2018 DNA directly by single and double strand breaks or indirectly by reactive oxygen species (ROS), which causes injury to biomolecules, including DNA.2 A majo…”
BackgroundPandey, B. N., Gordon, D. M., Toledo, S. M. D., Pain, D., & Azzam, E. I. (2006) · Antioxidants and Redox Signaling · doi:10.1089/ars.2006.8.1253 · Cited by 48
“In contrast, oxidative stress generated by radiation-induced perturbations in oxidative metabolism induces damage to critical biomolecules, including DNA, long after radiation exposure (46).”
Saada, H. N., Said, U. Z., Meky, N. H., & El-Azime, A. S. A. (2008) · Phytotherapy Research · doi:10.1002/ptr.2684 · Cited by 47
“If this damage is irreparable, then injury, mutagenesis, carcinogenesis, accelerated senescence and cell death can occur (Spitz et al., 2004).”
Background
Metadata
- Authors
- Spitz, D. R., Azzam, E. I., Jian Li, J., & Gius, D.
- Affiliations
- University of Iowa (US)
- Rutgers New Jersey Medical School (US)
- National Institutes of Health (US)
- Corresponding author
- Spitz, Douglas R.
- Venue
- Cancer and Metastasis Reviews
- Published
- 2004-08
- Volume
- 23
- Issue
- 3-4
- Pages
- 311-322
- ISSN
- 0167-7659 (ISSN-L)
- 1573-7233
- OpenAlex
- W2023627397
- Cited by
- 710
- References
- 105
- Citations by year
- 2026: 19 · 2025: 24 · 2024: 21 · 2023: 33 · 2022: 27 · 2021: 41 · 2020: 47 · 2019: 46 · 2018: 50 · 2017: 41 · 2016: 38 · 2015: 21 · 2014: 33 · 2013: 47 · 2012: 43
- FWCI
- 2.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Cancer and Metastasis Reviews (publishedVersion)
- PubMed (publishedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- ionizing radiation, redox signaling, free radicals, radiation-induced oxidative damage, radiation adaptive response, bystander effect, cell cycle disruption, radiosensitization, genomic instability, inflammation, fibrosis, transcription factor activation, gene expression
- MeSH terms
- Animals, Cell Communication, Humans, Oxidation-Reduction, Radiation, Ionizing, Signal Transduction, Oxidative Stress, Genomic Instability
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