Metabolic oxidation/reduction reactions and cellular responses to ionizing radiation: A unifying concept in stress response biology

Spitz, Douglas R.; Azzam, Edouard I.; Jian Li, Jian; Gius, David

doi:10.1023/b:canc.0000031769.14728.bc

Cited by 710Effects of Radiation ExposureRedox biology and oxidative stressBioactive Compounds and Antitumor Agents

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Metabolic oxidation/reduction reactions and cellular responses to ionizing radiation: A unifying concept in stress response biology

Spitz, Douglas R., Azzam, Edouard I., Jian Li, Jian, Gius, David·2004·Cancer and Metastasis Reviews

DOI 10.1023/b:canc.0000031769.14728.bc

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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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Generation of ROS is an important mediator of cellular alterations caused by radiation exposure, including mucositis.
“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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Lifestyle, oxidative stress, and antioxidants: Back and forth in the pathophysiology of chronic diseases
Sharifi-Rad, M., Anil Kumar, N. V., Zucca, P., Varoni, E. M., Dini, L., Panzarini, E., Rajkovic, J., Tsouh Fokou, P. V., Azzini, E., Peluso, I., et al. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00694 · Cited by 1,971
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Radiotherapy and Immunotherapy Promote Tumoral Lipid Oxidation and Ferroptosis via Synergistic Repression of SLC7A11
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“Radiotherapy stochastically induces oxidative damage in all cellular compartments, including the lipid membrane (10, 11).”
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SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress
Kim, H.-S., Patel, K., Muldoon-Jacobs, K., Bisht, K. S., Aykin-Burns, N., Pennington, J. D., van der Meer, R., Nguyen, P., Savage, J., Owens, K. M., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2009.11.023 · Cited by 785
“Cellular exposure to exogenous genotoxic stress, such as IR, has previously been shown to induce chromosomal aberrations, and one mechanism accounting for this observation has been hypothesized to involve increased intracellular superoxide levels (Spitz et al., 2004).”
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Oxidative stress and inflammation in the pathogenesis of neurological disorders: Mechanisms and implications
Dash, U. C., Bhol, N. K., Swain, S. K., Samal, R. R., Nayak, P. K., Raina, V., Panda, S. K., Kerry, R. G., Duttaroy, A. K., & Jena, A. B. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.10.004 · Cited by 806
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Combination strategies to maximize the benefits of cancer immunotherapy
Zhu, S., Zhang, T., Zheng, L., Liu, H., Song, W., Liu, D., Li, Z., & Pan, C.-X. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01164-5 · Cited by 654
“In addition to direct DNA damage, the presence of oxygen and generation of ROS are critical for radiation induced tissue injury [66].”
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Oxidative Stress and Pathogenesis of Inflammatory Bowel Disease: An Epiphenomenon or the Cause?
Rezaie, A. R., Parker, R. D., & Abdollahi, M. R. (2007) · Digestive Diseases and Sciences · doi:10.1007/s10620-006-9622-2 · Cited by 591
“Oxidative stress is a potential etiological and/or triggering factor for IBD, because the detrimental effects of reactive oxygen molecules (ROM) have been well established in the inflammation process [2].”
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Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation
Lee, S. Y., Jeong, E. K., Ju, M. K., Jeon, H. M., Kim, M. Y., Kim, C. H., Park, H. G., Han, S. I., & Kang, H. S. (2017) · Molecular Cancer · doi:10.1186/s12943-016-0577-4 · Cited by 586
The Many Functions of APE1/Ref-1: Not Only a DNA Repair Enzyme
Tell, G., Quadrifoglio, F., Tiribelli, C., & Kelley, M. R. (2008) · Antioxidants and Redox Signaling · doi:10.1089/ars.2008.2194 · Cited by 515
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The Linear No-Threshold Relationship Is Inconsistent with Radiation Biologic and Experimental Data
Tubiana, M., Feinendegen, L. E., Yang, C., & Kaminski, J. (2009) · Radiology · doi:10.1148/radiol.2511080671 · Cited by 507
Fundamental Biological Features of Spaceflight: Advancing the Field to Enable Deep-Space Exploration
Afshinnekoo, E., Scott, R. T., MacKay, M. J., Pariset, E., Cekanaviciute, E., Barker, R. J., Gilroy, S., Hassane, D. C., Smith, S. M., Zwart, S. R., et al. (2020) · Cell · doi:10.1016/j.cell.2020.10.050 · Cited by 496
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Roles of Reactive Oxygen Species and Antioxidants in Ovarian Toxicity1
Devine, P. J., Perreault, S. D., & Luderer, U. (2011) · Biology of Reproduction · doi:10.1095/biolreprod.111.095224 · Cited by 422
Reactive Oxygen Species in Normal and Tumor Stem Cells
Zhou, D., Shao, L., & Spitz, D. R. (2014) · Advances in cancer research · doi:10.1016/b978-0-12-420117-0.00001-3 · Cited by 411
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Multiple roles of cytochrome c oxidase in mammalian cells under action of red and IR‐A radiation
Karu, T. I. (2010) · IUBMB Life · doi:10.1002/iub.359 · Cited by 394
“metabolic oxidation/reduction reactions and cellular responses to ionizing radiation supports this suggestion (27).”
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Effects of ionizing radiation on mitochondria
Kam, W. W.-Y., & Banati, R. B. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.07.024 · Cited by 386
Cerium oxide nanoparticles protect gastrointestinal epithelium from radiation-induced damage by reduction of reactive oxygen species and upregulation of superoxide dismutase 2
Colon, J. F., Hsieh, N., Ferguson, A., Kupelian, P., Seal, S., Jenkins, D. W., & Baker, C. H. (2010) · Nanomedicine Nanotechnology Biology and Medicine · doi:10.1016/j.nano.2010.01.010 · Cited by 381
“Although it had been assumed that the initial oxidative damage caused by the free radicals was responsible for the alterations in intracellular processes after irradiation, there is increasing evidence that these free radicals also function in intracellular metabolic oxidation-reduction reactions and might contribute…”
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Estresse oxidativo: conceito, implicações e fatores modulatórios
Barbosa, K. B. F., Costa, N. M. B., Alfenas, R. D. C. G., de Paula, S. O., Minim, V. P. R., & Bressan, J. (2010) · Revista de Nutrição · doi:10.1590/s1415-52732010000400013 · Cited by 357
DNA damage foci: Meaning and significance
Rothkamm, K., Barnard, S. G. R., Moquet, J., Ellender, M., Rana, Z., & Burdak‐Rothkamm, S. (2015) · Environmental and Molecular Mutagenesis · doi:10.1002/em.21944 · Cited by 345
“The RIBE can potentially be interpreted as part of a general genotoxic stress response [Spitz et al., 2004].”
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An integrated physico-chemical approach for explaining the differential impact of FLASH versus conventional dose rate irradiation on cancer and normal tissue responses
Spitz, D. R., Buettner, G. R., Petronek, M. S., St‐Aubin, J., Flynn, R. T., Waldron, T. J., & Limoli, C. L. (2019) · Radiotherapy and Oncology · doi:10.1016/j.radonc.2019.03.028 · Cited by 310
mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis
Iglesias-Bartolome, R., Patel, V., Cotrim, A., Leelahavanichkul, K., Molinolo, A. A., Mitchell, J. B., & Gutkind, J. S. (2012) · Cell Stem Cell · doi:10.1016/j.stem.2012.06.007 · Cited by 284
“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., 2005, 2007).”
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Redox regulation in stem-like cancer cells by CD44 variant isoforms
Nagano, O., Okazaki, S., & Saya, H. (2013) · Oncogene · doi:10.1038/onc.2012.638 · Cited by 280
Zinc oxide nanoparticles induce apoptosis and autophagy in human ovarian cancer cells
Bai, D.-P., Zhang, X., Zhang, G., Huang, Y.-F., & Gurunathan, S. (2017) · International Journal of Nanomedicine · doi:10.2147/ijn.s140071 · Cited by 281
“50 With the enrichment of O 2 - and H 2 O 2 , oxidative stress occurs and the cellular redox balance is impaired, resulting in oxidative damage to cells.”
Total body irradiation causes residual bone marrow injury by induction of persistent oxidative stress in murine hematopoietic stem cells
Wang, Y., Liu, L., Pazhanisamy, S. K., Li, H., Meng, A., & Zhou, D. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.11.005 · Cited by 273
Cyclin B1/CDK1-regulated mitochondrial bioenergetics in cell cycle progression and tumor resistance
Xie, B., Wang, S., Jiang, N., & Li, J. J. (2018) · Cancer Letters · doi:10.1016/j.canlet.2018.11.019 · Cited by 267
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Protection against chemotherapy- and radiotherapy-induced side effects: A review based on the mechanisms and therapeutic opportunities of phytochemicals
Liu, Y., Wang, X., He, D., & Cheng, Y. (2020) · Phytomedicine · doi:10.1016/j.phymed.2020.153402 · Cited by 269
Cancer stem cells and radioresistance
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“As mentioned above, therapeutic IR causes DNA damage and generates oxidative stress in cells, and this leads to the activation of specifi c signaling pathways in the irradiated cells (Spitz et al. 2004).”
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Wild-type and mutated IDH1/2 enzymes and therapy responses
Molenaar, R. J., Maciejewski, J. P., Wilmink, J. W., & Noorden, C. J. F. V. (2018) · Oncogene · doi:10.1038/s41388-017-0077-z · Cited by 249
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Role of Mitochondria in Radiation Responses: Epigenetic, Metabolic, and Signaling Impacts
Averbeck, D., & Rodriguez‐Lafrasse, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222011047 · Cited by 255
Radiation-Induced Normal Tissue Damage: Oxidative Stress and Epigenetic Mechanisms
Wei, J., Wang, B., Wang, H., Meng, L., Zhao, Q., Li, X., Xin, Y., & Jiang, X. M. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/3010342 · Cited by 225
“In recent years, studies have shown that the oxidation/reduction (redox) system was associated with several types of damage after radiation exposure [2].”
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Resveratrol ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice
Zhang, H., Zhai, Z., Wang, Y., Zhang, J., Wu, H., Wang, Y., Li, C., Li, D., Lu, L., Wang, X., et al. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.10.530 · Cited by 207
“Increased production of ROS by irradiated cells has been largely attributed to the dysfunction of mitochondria [26, 27].”
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Interactions between TGF-β1, canonical WNT/β-catenin pathway and PPAR γ in radiation-induced fibrosis
Vallée, A., Lecarpentier, Y., Guillevin, R., & Vallée, J.-N. (2017) · Oncotarget · doi:10.18632/oncotarget.21234 · Cited by 210
“Oxidative stress and inflammation are involved in radiation-induced brain injury [271, 272].”
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Regulation of MnSOD Enzymatic Activity by Sirt3 Connects the Mitochondrial Acetylome Signaling Networks to Aging and Carcinogenesis
Tao, R., Vassilopoulos, A., Parisiadou, L., Yan, Y., & Gius, D. (2014) · Antioxidants & Redox Signaling · doi:10.1089/ars.2013.5482 · Cited by 194
“mitochondrial ROS through the conversion of superoxide to hydrogen peroxide and ultimately to H2O by catalase (78).”
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Oxidative damage pathways in relation to normal tissue injury
Zhao, W., Diz, D. I., & Robbins, M. E. C. (2007) · British Journal of Radiology · doi:10.1259/bjr/18237646 · Cited by 205
SIRT3 Is a Mitochondrial Tumor Suppressor: A Scientific Tale That Connects Aberrant Cellular ROS, the Warburg Effect, and Carcinogenesis
Haigis, M. C., Deng, C., Finley, L. W. S., Kim, H., & Gius, D. R. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-3633 · Cited by 196
Holo-lactoferrin: the link between ferroptosis and radiotherapy in triple-negative breast cancer
Zhang, Z., Lu, M., Chen, C., Tong, X., Li, Y., Yang, K., Lv, H., Xu, J., & Qin, L. (2021) · Theranostics · doi:10.7150/thno.52028 · Cited by 194
“It not only induces DNA damage, but also causes oxidative damage to the cell membrane and leads to ferroptosis of cancer cells [65].”
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The Epidermal Growth Factor Receptor: A Role in Repair of Radiation-Induced DNA Damage
Chen, D. J., & Nirodi, C. S. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-1610 · Cited by 197
“Exposure to ionizing radiation leads to the rapid production of highly reactive hydroxyl ion, superoxide, and organic radicals which react with oxygen to form reactive oxygen species including H2O2 and organic peroxides that chemically react with DNA to produce DNA damage (2).”
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DNA oxidation: Investigating its key role in environmental mutagenesis with the comet assay
Azqueta, A., Shaposhnikov, S. A., & Collins, A. R. (2008) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/j.mrgentox.2008.10.013 · Cited by 196
Redox Signaling in Cancer Biology
Gius, D. R., & Spitz, D. R. (2006) · Antioxidants and Redox Signaling · doi:10.1089/ars.2006.8.1249 · Cited by 191
Mutation of Succinate Dehydrogenase Subunit C Results in Increased O2·−, Oxidative Stress, and Genomic Instability
Slane, B. G., Aykin‐Burns, N., Smith, B. J., Kalen, A. L., Goswami, P. C., Domann, F. E., & Spitz, D. R. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-0833 · Cited by 188
“and H2O2) could be related to the DNA-damaging processes causing aging and carcinogenesis (3, 10, 11, 30).”
BackgroundInfluential
Mitochondrial dysfunction, a probable cause of persistent oxidative stress after exposure to ionizing radiation
Yoshida, T., Goto, S., Kawakatsu, M., Urata, Y., & Li, T. (2011) · Free Radical Research · doi:10.3109/10715762.2011.645207 · Cited by 185
“Gamma-ray radiation decreased the activity of NADH dehydrogenase It is generally accepted that oxidative stress persists over a long period of time after exposure to irradiation [29].”
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Mitochondrial dysfunction, persistently elevated levels of reactive oxygen species and radiation-induced genomic instability: a review
J.Kim, G., Chandrasekaran, K., & Morgan, W. F. (2006) · Mutagenesis · doi:10.1093/mutage/gel048 · Cited by 181
Antioxidant Intake and Antitumor Therapy: Toward Nutritional Recommendations for Optimal Results
Mut‐Salud, N., Alvarez, P. J., Garrido, J. M., Carrasco, E., Aránega, A., & Rodríguez‐Serrano, F. (2015) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/6719534 · Cited by 187
Radioprotection in Normal Tissue and Delayed Tumor Growth by Blockade of CD47 Signaling
Maxhimer, J. B., Soto‐Pantoja, D. R., Ridnour, L. A., Shih, H. B., DeGraff, W., Tsokos, M., Wink, D. A., Isenberg, J. S., & Roberts, D. D. (2009) · Science Translational Medicine · doi:10.1126/scitranslmed.3000139 · Cited by 176
Radiation-induced skin injury: pathogenesis, treatment, and management
Yang, X., Ren, H., Guo, X., Hu, C., & Jie, F. (2020) · Aging · doi:10.18632/aging.103932 · Cited by 172
“com 23381 AGING reactive nitrogen and oxygen species (RNS/ROS) for the radiolysis of water [25].”
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Role of the Multifunctional DNA Repair and Redox Signaling Protein Ape1/Ref-1 in Cancer and Endothelial Cells: Small-Molecule Inhibition of the Redox Function of Ape1
Luo, M., Delaplane, S., Jiang, A., Reed, A. M., He, Y., Fishel, M. L., Nyland, R. L., Borch, R. F., Qiao, X., Georgiadis, M. M., et al. (2008) · Antioxidants and Redox Signaling · doi:10.1089/ars.2008.2120 · Cited by 167
“Finally, blocking the activity of Ape1 after IR has lead to an increase in tumor cell killing (37, 68, 73).”
Radiation–Induced Signaling Results in Mitochondrial Impairment in Mouse Heart at 4 Weeks after Exposure to X-Rays
Barjaktarović, Ž., Schmaltz, D., Shyla, A., Azimzadeh, O., Schulz, S., Haagen, J., Dörr, W., Sarioglu, H., Schäfer, A., Atkinson, M. J., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027811 · Cited by 168
“It has been suggested that persistent changes in oxidative metabolism may mediate the responses to ionizing radiation, ultimately leading to inflammation and cardiovascular disease [23,24].”
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NF-κB-MediatedHER2Overexpression inRadiation-Adaptive Resistance
Cao, N., Li, S., Wang, Z., Ahmed, K. M., Degnan, M. E., Fan, M., Dynlacht, J. R., & Li, J. J. (2008) · Radiation Research · doi:10.1667/rr1472.1 · Cited by 162
“It is well documented that NF-B is activated by radiation ( 46 , 47), and NF-B is now shown to bind directly to the HER2 promoter, resulting in HER2 overexpression and tumor adaptive radioresistance.”
Background
Hydrogen therapy attenuates irradiation-induced lung damage by reducing oxidative stress
Terasaki, Y., Ohsawa, I., Terasaki, M., Takahashi, M., Kunugi, S., Kang, D., Urushiyama, H., Amenomori, S., Kaneko-Togashi, M., Kuwahara, N., et al. (2011) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00008.2011 · Cited by 162
“In fact, ROS scavengers have been documented to reduce oxidative lung injury resulting from ionizing radiation (38, 39).”
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Review and evaluation of updated research on the health effects associated with low-dose ionising radiation
Dauer, L. T., Brooks, A. L., Hoel, D. G., Morgan, W. F., Stram, D. O., & Tran, P. (2010) · Radiation Protection Dosimetry · doi:10.1093/rpd/ncq141 · Cited by 160
Long-Term Consequences of Radiation-Induced Bystander Effects Depend on Radiation Quality and Dose and Correlate with Oxidative Stress
Buonanno, M., de Toledo, S. M., Pain, D., & Azzam, E. I. (2011) · Radiation Research · doi:10.1667/rr2461.1 · Cited by 159
A Role for Mitochondrial Dysfunction in Perpetuating Radiation-Induced Genomic Instability
Kim, G. J., Fiskum, G. M., & Morgan, W. F. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3036 · Cited by 158
“a role in instability initiation and perpetuation (6).”
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Redox Control of the Survival of Healthy and Diseased Cells
Zhang, Y., Du, Y., Le, W., Wang, K., Kieffer, N., & Zhang, J. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3685 · Cited by 161
“For instance, mutagenesis studies using environmental factors such as ionizing radiation and xenobiotics, often result in the genesis of ROS in cells (49, 344).”
Consuming a Ketogenic Diet while Receiving Radiation and Chemotherapy for Locally Advanced Lung Cancer and Pancreatic Cancer: The University of Iowa Experience of Two Phase 1 Clinical Trials
Zahra, A., Fath, M. A., Opat, E., Mapuskar, K. A., Bhatia, S. K., Ma, D. C., Rodman, S. N., Snyders, T. P., Chenard, C. A., Eichenberger‐Gilmore, J. M., et al. (2017) · Radiation Research · doi:10.1667/rr14668.1 · Cited by 151
“Furthermore, radiation and chemotherapy induce various levels of oxidative stress causing cell damage (5, 6).”
Background
PD-1/PD-L1 immune checkpoint blockade in breast cancer: research insights and sensitization strategies
Jin, M., Fang, J., Peng, J., Wang, X., Xing, P., Jia, K., Hu, J., Wang, D., Ding, Y., Wang, X., et al. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02176-8 · Cited by 162
Redox Paradox: A Novel Approach to Therapeutics-Resistant Cancer
Chaiswing, L., Clair, W. H. S., & Clair, D. K. S. (2018) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7485 · Cited by 149
“IR can increase ROS production both by inducing extracellular water radiolysis and by causing intracellular metabolic changes or damage to mitochondria (16, 24, 314, 352).”
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Reduction–oxidation (redox) system in radiation-induced normal tissue injury: molecular mechanisms and implications in radiation therapeutics
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Ionizing radiation, antioxidant response and oxidative damage: A meta-analysis
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“…of increased concentrations of ROS, decreased activity of antioxidant enzymes, and genetic damage associatedwith increased background radiation (Spitz et al., 2004), especially when disease is followed by another medical condition, like malnutrition, inflammatory disease or respiratory…”
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Ovarian Toxicity from Reactive Oxygen Species
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“In addition to the direct ionization of DNA, ionizing radiation also ionizes water molecules, resulting in ROS formation, and leads to persistent increases in mitochondrial ROS production (Wiseman and Halliwell 1996; Spitz et al. 2004; Kim et al. 2006).”
Issues in Low Dose Radiation Biology: The Controversy Continues. A Perspective
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Reproductive hazards of space travel in women and men
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Metformin ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice
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P‐glycoprotein: So Many Ways to Turn It On
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Mitochondrial DNA : more than an evolutionary bystander
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Oxidative stress-induced apoptosis in neurons correlates with mitochondrial DNA base excision repair pathway imbalance
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Interactions of dietary carotenoids with activated (singlet) oxygen and free radicals: Potential effects for human health
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High hydrostatic pressure pre-treatment of whey proteins enhances whey protein hydrolysate inhibition of oxidative stress and IL-8 secretion in intestinal epithelial cells
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Adaptive Responses to Low-Dose/Low-Dose-Rate γ Rays in Normal Human Fibroblasts: The Role of Growth Architecture and Oxidative Metabolism
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Oxidative Stress Induced by Zearalenone in Porcine Granulosa Cells and Its Rescue by Curcumin In Vitro
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“Multiple enzyme systems are involved in ZEA toxicity, SOD1 in the cytoplasm dismutates O2 - to H2O2 and water, GPX1 and CAT then convert H2O2 to water (Fig 8).”
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Effects of phytochemicals on ionization radiation-mediated carcinogenesis and cancer therapy
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Increased sensitivity to radiochemotherapy in IDH1 mutant glioblastoma as demonstrated by serial quantitative MR volumetry
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Sirt3, Mitochondrial ROS, Ageing, and Carcinogenesis
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Melanin, a promising radioprotector: Mechanisms of actions in a mice model
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Altered redox status accompanies progression to metastatic human bladder cancer
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Nuclear Factor-κB and Manganese Superoxide Dismutase Mediate Adaptive Radioresistance in Low-Dose Irradiated Mouse Skin Epithelial Cells
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The Role of Peroxiredoxin II in Radiation-Resistant MCF-7 Breast Cancer Cells
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DNA is a fractal antenna in electromagnetic fields
Blank, M., & Goodman, R. (2011) · International Journal of Radiation Biology · doi:10.3109/09553002.2011.538130 · Cited by 100
“The cellular response to molecular damage, the stress response, is also found in the middle of the ultraviolet (UV) range (Spitz et al. 2004) which is in the ionising range.”
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Space-type radiation induces multimodal responses in the mouse gut microbiome and metabolome
Casero, D., Gill, K., Sridharan, V., Koturbash, I., Nelson, G. A., Hauer‐Jensen, M., Boerma, M., Braun, J. G., & Cheema, A. K. (2017) · Microbiome · doi:10.1186/s40168-017-0325-z · Cited by 99
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Flavonoids of Rosa roxburghii Tratt exhibit radioprotection and anti-apoptosis properties via the Bcl-2(Ca2+)/Caspase-3/PARP-1 pathway
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The Nrf2/GCH1/BH4 Axis Ameliorates Radiation-Induced Skin Injury by Modulating the ROS Cascade
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“Ionizing radiation promotes reactive nitrogen and oxygen species (RNS/ROS) production due to radiolysis of water and direct ionization of target molecules (Leach et al., 2001, Spitz et al., 2004).”
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Mitochondrial Complex II Dysfunction Can Contribute Significantly to Genomic Instability after Exposure to Ionizing Radiation
Dayal, D., Martin, S. M., Owens, K. M., Aykin‐Burns, N., Zhu, Y., Amutha, B., Pain, D., Limoli, C. L., Goswami, P. C., Domann, F. E., et al. (2009) · Radiation Research · doi:10.1667/rr1617.1 · Cited by 96
Concepts and challenges in cancer risk prediction for the space radiation environment
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“Long-term changes are also evident in cells, including welldocumented stress and oxidative signaling that may be mediated by mitochondrial dysfunction (Spitz et al., 2004).”
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Glioblastoma Therapy Can Be Augmented by Targeting IDH1-Mediated NADPH Biosynthesis
Wahl, D. R., Dresser, J., Wilder-Romans, K., Parsels, J. D., Zhao, S. G., Davis, M. A., Zhao, L., Kachman, M. T., Wernisch, S., Burant, C., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-2008 · Cited by 97
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An assessment of techniques to manipulate oxidative stress in animals
Koch, R. E., & Hill, G. E. (2016) · Functional Ecology · doi:10.1111/1365-2435.12664 · Cited by 95
Role of the translationally controlled tumor protein in DNA damage sensing and repair
Zhang, J., de Toledo, S. M., Pandey, B. N., Guo, G., Pain, D., Hong Li, A., & Azzam, E. I. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1106300109 · Cited by 93
“S1A) is consistent with its role as a surveillance sentinel that guards against prolonged radiation-induced oxidative damage (29).”
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The Relationship between Reactive Oxygen Species and the cGAS/STING Signaling Pathway in the Inflammaging Process
Andrade, B., Jara‐Gutiérrez, C., Paz-Araos, M., Vázquez, M. C., Díaz, P., & Murgas, P. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232315182 · Cited by 95
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Redox modulation of the DNA damage response
Caputo, F., Vegliante, R., & Ghibelli, L. (2012) · Biochemical Pharmacology · doi:10.1016/j.bcp.2012.07.022 · Cited by 95
“X-rays induce direct DNA breaks and H2O radiolysis, which results in ROS production; these ROS produce a second type of DNA lesions, increasing the overall damage [144].”
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Metabolic defects provide a spark for the epigenetic switch in cancer
Hitchler, M. J., & Domann, F. E. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.04.010 · Cited by 91
“These ideas have since been expanded by others to include metabolic and redox changes in cancer [1,3,21].”
Mechanisms for Tuning Engineered Nanomaterials to Enhance Radiation Therapy of Cancer
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NADPH oxidase mediates radiation-induced oxidative stress in rat brain microvascular endothelial cells
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“rapidly induced, and persist over time by self-amplification, they are considered as main mediators of sustained radiation-modifications of the microenvironment, in particular fibrosis (desmoplastic reaction) (36).”
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Thiol regulation by Mn porphyrins, commonly known as SOD mimics
Batinic-Haberle, I., & Tome, M. E. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101139 · Cited by 88
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Low- and moderate-dose non-cancer effects of ionizing radiation in directly exposed individuals, especially circulatory and ocular diseases: a review of the epidemiology
Little, M. P., Azizova, T. V., & Hamada, N. (2021) · International Journal of Radiation Biology · doi:10.1080/09553002.2021.1876955 · Cited by 94
“…hypothesized that radiation may lead to changes in oxygen metabolism, resulting in long-lasting elevations in reactive oxygen species (ROS) and other parts of an inflammatory cascade (Spitz et al. 2004); there is evidence for long-lasting elevations in vascular ROS in the LSS (Nakachi et al. 2008).”
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Micro RNA responses to chronic or acute exposures to low dose ionizing radiation
Chaudhry, M. A., Omaruddin, R. A., Kreger, B. T., de Toledo, S. M., & Azzam, E. I. (2012) · Molecular Biology Reports · doi:10.1007/s11033-012-1589-9 · Cited by 84
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Ionizing Radiation Effects to the Cytoplasm
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Targeting of cellular redox metabolism for mitigation of radiation injury
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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.
ORCID: Spitz, Douglas R.
Azzam, Edouard I.
Gius, David
Venue: Cancer and Metastasis Reviews
Publisher: Springer Science and Business Media LLC
Published: 2004-08
Volume: 23
Issue: 3-4
Pages: 311-322
ISSN: 0167-7659 (ISSN-L)
1573-7233
DOI: 10.1023/b:canc.0000031769.14728.bc
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: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
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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Metabolic oxidation/reduction reactions and cellular responses to ionizing radiation: A unifying concept in stress response biology

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