Radiation-induced Death Research Articles

GSK-3β Inhibition Attenuates LPS-Induced Death but Aggravates Radiation-Induced Death via Down-Regulation of IL-6

Background: Exposure of high dose ionizing radiation is lethal. Signal pathways involved in radiation biology reaction still remain illdefined. Lipopolysaccharides (LPS), the ligands of Toll-like receptor 4(TLR4), could elicit strong immune responses. Glycogen synthase kinase-3β(GSK-3β) promotes the production of inflammatory molecules and cell migration. Inhibition of GSK-3β provides protection against inflammation in animal models. The aim of the study was to investigate role of GSK-3β in LPS shock and ionizing radiation. Methods: WT or IL-6^-/-mice or cells were pretreated with SB216763, a GSK-3β inhibitor, and survival of the mice was determined. Cell viability was assayed by Cell Counting Kit. Apoptosis was assayed by Annexin V-PI double staining. Serum concentrations of IL-6 and TNF-α were determined by ELISA. Results: SB216763 attenuated LPS induced mice or cell death but aggravated radiation induced mice or cell death. SB216763 reduced IL-6, but not TNF-α levels in vivo. IL-6^-/- mice were more resistant to LPS-induced death but less resistant to radiation-induced death than wild type mice. Conclusions: Inhibition of GSK-3β conferred resistance to LPS shock but fostered death induced by ionizing radiation. Inhibition of GSK-3β was effective by reducing IL-6.

Inhibition of Colonic Tumor Growth by the Selective SGK Inhibitor EMD638683

Background: The serum and glucocorticoid inducible kinase SGK1, which was originally cloned from mammary tumor cells, is highly expressed in some but not all tumors. SGK1 confers survival to several tumor cells. Along those lines, the number of colonic tumors following chemical carcinogenesis was decreased in SGK1 knockout mice. Recently, a highly selective SGK inhibitor (EMD638683) has been developed. The present study explored whether EMD638683 affects survival of colon carcinoma cells in vitro and impacts on development of colonic tumors in vivo. Methods: Colon carcinoma (Caco-2) cells were exposed to EMD638683 with or without exposure to radiation (3 Gray) and cell volume was estimated from forward scatter, phosphatidylserine exposure from annexin V binding, mitochondrial potential from JC-9 fluorescence, caspase 3 activity from CaspGlow Fluorescein staining, DNA degradation from propidium iodide staining as well as late apoptosis from annexin-V FITC and propidium iodide double staining. In vivo tumor growth was determined in wild type mice subjected to chemical carcinogenesis (intraperitoneal injection of 20 mg/kg 1,2-dimethylhydrazine followed by three cycles of 30 g/L synthetic dextran sulfate sodium in drinking water for 7 days). Results: EMD638683 treatment significantly augmented the radiation-induced decrease of forward scatter, increase of phosphatidylserine exposure, decrease of mitochondrial potential, increase of caspase 3 activity, increase of DNA fragmentation and increase of late apoptosis. The in vivo development of tumors following chemical carcinogenesis was significantly blunted by treatment with EMD638683. Conclusions: EMD638683 promotes radiation-induced suicidal death of colon tumor cells in vitro and decreases the number of colonic tumors following chemical carcinogenesis in vivo.

Cell-type, Dose, and Mutation-type Specificity Dictate Mutant p53 Functions In Vivo

The specific roles of mutant p53's dominant-negative (DN) or gain-of-function (GOF) properties in regulating acute response and long-term tumorigenesis is unclear. Using "knockin" mouse strains expressing varying R246S mutant levels, we show that the DN effect on transactivation is universally observed after acute p53 activation, whereas the effect on cellular outcome is cell-type specific. Reducing mutant p53 levels abrogated the DN effect. Mutant p53's DN effect protected against radiation-induced death but did not accentuate tumorigenesis. Furthermore, the R246S mutant did not promote tumorigenesis compared to p53(-/-) mice in various models, even when MDM2 is absent, unlike the R172H mutant. Together, these data demonstrate that mutant p53's DN property only affects acute responses, whereas GOF is not universal, being mutation-type specific.

Revisiting emergency anti-apoptotic cytokinotherapy: erythropoietin synergizes with stem cell factor, FLT-3 ligand, trombopoietin and interleukin-3 to rescue lethally-irradiated mice

We have re-evaluated the benefit of using erythropoietin (Epo) as a pleiotropic cytokine to counteract hematological and extra-hematological toxicity following lethal irradiation. B6D2F1 mice were exposed to a dose of 9 Gy gamma radiation resulting in 90% mortality at 30 days, and then injected with stem cell factor, FLT-3 ligand, thrombopoietin and interleukin-3 [i.e. SFT3] at two and 24 hours with or without Epo (1,000 IU/kg) at 2 hours and day 8. As controls, two groups of irradiated mice were given only Epo or Phosphate-buffered saline. Epo synergized with SFT3 to rescue lethally-irradiated mice from radiation-induced death (survival: 60%, 95% and 5% respectively for SFT3, SFT3+Epo and controls at 30 days, p<0.05), whereas Epo alone exhibited no protective effect. Hematopoietic parameters did not differ significantly between SFT3 and SFT3+Epo groups during the animal death period. Some beneficial effects on gastro-intestinal toxicity were noticed following administration of Epo, although lung, liver and kidney were not protected. Further studies are necessary to understand fully the mechanisms involved in these effects of Epo in order to optimize treatment with cytokines following high-dose irradiation.

PAI-1-Dependent Endothelial Cell Death Determines Severity of Radiation-Induced Intestinal Injury

Normal tissue toxicity still remains a dose-limiting factor in clinical radiation therapy. Recently, plasminogen activator inhibitor type 1 (SERPINE1/PAI-1) was reported as an essential mediator of late radiation-induced intestinal injury. However, it is not clear whether PAI-1 plays a role in acute radiation-induced intestinal damage and we hypothesized that PAI-1 may play a role in the endothelium radiosensitivity. In vivo, in a model of radiation enteropathy in PAI-1 −/− mice, apoptosis of radiosensitive compartments, epithelial and microvascular endothelium was quantified. In vitro, the role of PAI-1 in the radiation-induced endothelial cells (ECs) death was investigated. The level of apoptotic ECs is lower in PAI-1 −/− compared with Wt mice after irradiation. This is associated with a conserved microvascular density and consequently with a better mucosal integrity in PAI-1 −/− mice. In vitro, irradiation rapidly stimulates PAI-1 expression in ECs and radiation sensitivity is increased in ECs that stably overexpress PAI-1, whereas PAI-1 knockdown increases EC survival after irradiation. Moreover, ECs prepared from PAI-1 −/− mice are more resistant to radiation-induced cell death than Wt ECs and this is associated with activation of the Akt pathway. This study demonstrates that PAI-1 plays a key role in radiation-induced EC death in the intestine and suggests that this contributes strongly to the progression of radiation-induced intestinal injury.

Bactericidal/Permeability-Increasing Protein (rBPI 21 ) and Fluoroquinolone Mitigate Radiation-Induced Bone Marrow Aplasia and Death

Identification of safe, effective treatments to mitigate toxicity after extensive radiation exposure has proven challenging. Only a limited number of candidate approaches have emerged, and the U.S. Food and Drug Administration has yet to approve any agent for a mass-casualty radiation disaster. Because patients undergoing hematopoietic stem cell transplantation undergo radiation treatment that produces toxicities similar to radiation-disaster exposure, we studied patients early after such treatment to identify new approaches to this problem. Patients rapidly developed endotoxemia and reduced plasma bactericidal/permeability-increasing protein (BPI), a potent endotoxin-neutralizing protein, in association with neutropenia. We hypothesized that a treatment supplying similar endotoxin-neutralizing activity might replace the BPI deficit and mitigate radiation toxicity and tested this idea in mice. A single 7-Gy radiation dose, which killed 95% of the mice by 30 days, was followed 24 hours later by twice-daily, subcutaneous injections of the recombinant BPI fragment rBPI21 or vehicle alone for 14 or 30 days, with or without an oral fluoroquinolone antibiotic with broad-spectrum antibacterial activity, including that against endotoxin-bearing Gram-negative bacteria. Compared to either fluoroquinolone alone or vehicle plus fluoroquinolone, the combined rBPI21 plus fluoroquinolone treatment improved survival, accelerated hematopoietic recovery, and promoted expansion of stem and progenitor cells. The observed efficacy of rBPI21 plus fluoroquinolone initiated 24 hours after lethal irradiation, combined with their established favorable bioactivity and safety profiles in critically ill humans, suggests the potential clinical use of this radiation mitigation strategy and supports its further evaluation.

Effects of N-acetyl- l-cysteine on fish hepatoma cells treated with mercury chloride and ionizing radiation

Organisms are exposed to natural radiations from cosmic or terrestrial origins. Furthermore the combined action of radiation with various chemicals is an inevitable feature of modern life. Radiation is known to cause cell death, mainly due to its ability to produce reactive oxygen species in cells. N-acetyl- l-cysteine (NAC) is a well-known sulfhydryl-containing antioxidant whose role in radioprotection has been reported. Synergistic effects of radiation and mercury chloride on human cells was previously reported by the authors. Based on the previous report, this study was designed to assess the synergistic effects of radiation and mercury chloride on fish hepatoma cells, as well as to investigate the protective effects of NAC on the cells. The cytotoxicity of radiation was enhanced in the presence of mercury chloride. NAC in lower concentrations prevented cells from death after irradiation with lower doses (<300 Gy) while it did not prevent cells from radiation-induced death after irradiation with higher doses (300, 500 Gy). The intracellular glutathione (GSH) levels significantly decreased after irradiation while the combined treatment of NAC and radiation alleviated the decrease in the GSH levels. The investigations give a clue for the action mechanism of synergistic or protective effects of NAC on the cells. Due to their high resistance to ionizing radiation, the PLHC-1 cells can be effectively used as a screening tool for assessing the combined effects of radiation with toxic chemicals.

A mitochondria-targeted inhibitor of cytochrome c peroxidase mitigates radiation-induced death.

The risk of radionuclide release in terrorist acts or exposure of healthy tissue during radiotherapy demand potent radioprotectants/radiomitigators. Ionizing radiation induces cell death by initiating the selective peroxidation of cardiolipin in mitochondria by the peroxidase activity of its complex with cytochrome c leading to release of hemoprotein into the cytosol and commitment to the apoptotic program. Here we design and synthesize mitochondria-targeted triphenylphosphonium-conjugated imidazole-substituted oleic and stearic acids which blocked peroxidase activity of cytochrome c/cardiolipin complex by specifically binding to its heme-iron. We show that both compounds inhibit pro-apoptotic oxidative events, suppress cyt c release, prevent cell death, and protect mice against lethal doses of irradiation. Significant radioprotective/radiomitigative effects of imidazole-substituted oleic acid are observed after pretreatment of mice from 1 hr before through 24 hrs after the irradiation.

Curcumin-loaded PLGA microspheres with enhanced radioprotection in mice

Curcumin, known for its ability to scavenge superoxide and hydroxy radicals, has been shown to inhibit lipid peroxide formation in-vitro. In-vivo studies indicate that pre-irradiation administration of curcumin reduces radiation-induced toxicity and death in mice. Poly(lactide-co-glycolide) (PLGA), is one of the most widely used synthetic polymer, for controlled release preparations. Since curcumin is insoluble in water, curcumin microspheres using PLGA polymer were developed. Microencapsuation allowed slower release of curcumin, enhanced stability and greater radioprotective efficacy compared with plain curcumin.

Radiosensitization of Oropharyngeal Squamous Cell Carcinoma Cells by Human Papillomavirus 16 Oncoprotein E6∗I

Patients with oropharyngeal squamous cell carcinoma (OSCC) whose disease is associated with high-risk human papillomavirus (HPV) infection have a significantly better outcome than those with HPV-negative disease, but the reasons for the better outcome are not known. We postulated that they might relate to an ability of HPV proteins to confer a better response to radiotherapy, a commonly used treatment for OSCC. We stably expressed the specific splicing-derived isoforms, E6∗I and E6∗II, or the entire E6 open reading frame (E6total), which gives rise to both full length and E6∗I isoforms, in OSCC cell lines. Radiation resistance was measured in clonogenicity assays, p53 activity was measured using transfected reporter genes, and flow cytometry was used to analyze cell cycle and apoptosis. E6∗I and E6total sensitized the OSCC cells to irradiation, E6∗I giving the greatest degree of radiosensitization (approximately eightfold lower surviving cell fraction at 10 Gy), whereas E6∗II had no effect. In contrast to radiosensitivity, E6∗I was a weaker inhibitor than E6total of tumor suppressor p53 transactivator activity in the same cells. Flow cytometric analyses showed that irradiated E6∗I expressing cells had a much higher G2M:G1 ratio than control cells, indicating that, after G2, cells were diverted from the cell cycle to programmed cell death. This study supports a role for E6∗I in the enhanced responsiveness of HPV-positive oropharyngeal carcinomas to p53-independent radiation-induced death.

Prevention and Mitigation of Acute Death of Mice after Abdominal Irradiation by the Antioxidant N-Acetyl-cysteine (NAC)

Gastrointestinal (GI) injury is a major cause of acute death after total-body exposure to large doses of ionizing radiation, but the cellular and molecular explanations for GI death remain dubious. To address this issue, we developed a murine abdominal irradiation model. Mice were irradiated with a single dose of X rays to the abdomen, treated with daily s.c. injection of N-acetyl-l-cysteine (NAC) or vehicle for 7 days starting either 4 h before or 2 h after irradiation, and monitored for up to 30 days. Separately, mice from each group were assayed 6 days after irradiation for bone marrow reactive oxygen species (ROS), ex vivo colony formation of bone marrow stromal cells, and histological changes in the duodenum. Irradiation of the abdomen caused dose-dependent weight loss and mortality. Radiation-induced acute death was preceded not only by a massive loss of duodenal villi but also, surprisingly, abscopal suppression of stromal cells and elevation of ROS in the nonirradiated bone marrow. NAC diminished these radiation-induced changes and improved 10- and 30-day survival rates to >50% compared with <5% in vehicle-treated controls. Our data establish a central role for abscopal stimulation of bone marrow ROS in acute death in mice after abdominal irradiation.

Deletion of Puma protects hematopoietic stem cells and confers long-term survival in response to high-dose γ-irradiation

AbstractMolecular paradigms underlying the death of hematopoietic stem cells (HSCs) induced by ionizing radiation are poorly defined. We have examined the role of Puma (p53 up-regulated mediator of apoptosis) in apoptosis of HSCs after radiation injury. In the absence of Puma, HSCs were highly resistant to γ-radiation in a cell autonomous manner. As a result, Puma-null mice or the wild-type mice reconstituted with Puma-null bone marrow cells were strikingly able to survive for a long term after high-dose γ-radiation that normally would pose 100% lethality on wild-type animals. Interestingly, there was no increase of malignancy in the exposed animals. Such profound beneficial effects of Puma deficiency were likely associated with better maintained quiescence and more efficient DNA repair in the stem cells. This study demonstrates that Puma is a unique mediator in radiation-induced death of HSCs. Puma may be a potential target for developing an effective treatment aimed to protect HSCs from lethal radiation.

Radiation-Induced Interleukin-6 Expression Through MAPK/p38/NF-κB Signaling Pathway and the Resultant Antiapoptotic Effect on Endothelial Cells Through Mcl-1 Expression With sIL6-Rα

To investigate the mechanism of interleukin-6 (IL-6) activity induced by ionizing radiation. Human umbilical vascular endothelial cells (HUVECs) were irradiated with different doses to induce IL-6. The IL-6 promoter assay and reverse transcriptase-polymerase chain reaction (RT-PCR) were used to examine transcriptional regulation. Specific chemical inhibitors, decoy double-stranded oligodeoxynucleotides, and Western blotting were conducted to investigate the signal transduction pathway. Recombinant soluble human IL-6 receptor alpha-chain (sIL6-Ralpha) and specific small interfering RNA were used to evaluate the biologic function of radiation-induced IL-6. Four grays of radiation induced the highest level of IL-6 protein. The promoter assay and RT-PCR data revealed that the induction of IL-6 was mediated through transcriptional regulation. The p38 inhibitor SB203580, by blocking nuclear factor-kappaB (NF-kappaB) activation, prevented both the transcriptional and translational regulation of radiation-induced IL-6 expression. The addition of sIL6-Ralpha rescued HUVECs from radiation-induced death in an IL-6 concentratio-dependent manner. The antiapoptotic effect of combined sIL6-Ralpha and radiation-induced IL-6 was inhibited by mcl-1-specific small interfering RNA. Radiation transcriptionally induces IL-6 expression in endothelial cells through mitogen-activated protein kinase/p38-mediated NF-kappaB/IkappaB (inhibitor of NF-kappaB) complex activation. In the presence of sIL6-Ralpha, radiation-induced IL-6 expression acts through Mcl-1 expression to rescue endothelial cells from radiation-induced death.

Modification of Mortality and Tumorigenesis by Tocopherol-mono-glucoside (TMG) Administered after X Irradiation in Mice and Rats

The effects of TMG [2-(alpha-d-glucopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol], a water-soluble vitamin E derivative, administered after irradiation on the mortality of X-irradiated mice and on the development of tumors in the mammary and pituitary glands in rats were investigated. When TMG (650 mg/kg) was administered intraperitoneally (i.p.) to C3H mice immediately after whole-body exposure to 7 Gy radiation, the 30-day survival was significantly higher than that of the control mice. The i.p. administration of TMG at 4 h after irradiation significantly improved survival compared to that of the controls, but administration 8 h after irradiation did not have a significant effect. Subcutaneous administration of TMG immediately after irradiation also decreased mortality significantly. When dams of lactating Wister rats were exposed to 1.5 Gy of X rays at day 21 after parturition and were then treated with diethylstilbestrol as a tumor promoter, the incidence of mammary tumors and pituitary tumors was increased compared to that in the nonirradiated control group. The administration of TMG (600 mg/kg, i.p.) after irradiation significantly reduced the incidence of mammary tumors and pituitary tumors. The number of rats that were free of both mammary and pituitary gland tumors was enhanced fourfold by TMG. These results suggest that TMG is effective in preventing radiation-induced bone marrow death in mice and in reducing mammary and pituitary tumors in rats even when it is administered after irradiation.

Role of Cell Cycle in Epidermal Growth Factor Receptor Inhibitor-Mediated Radiosensitization

Epidermal growth factor receptor (EGFR) inhibitors are increasingly used in combination with radiotherapy in the treatment of various EGFR-overexpressing cancers. However, little is known about the effects of cell cycle status on EGFR inhibitor-mediated radiosensitization. Using EGFR-overexpressing A431 and UMSCC-1 cells in culture, we found that radiation activated the EGFR and extracellular signal-regulated kinase pathways in quiescent cells, leading to progression of cells from G(1) to S, but this activation and progression did not occur in proliferating cells. Inhibition of this activation blocked S-phase progression and protected quiescent cells from radiation-induced death. To determine if these effects were caused by EGFR expression, we transfected Chinese hamster ovary (CHO) cells, which lack EGFR expression, with EGFR expression vector. EGFR expressed in CHO cells also became activated in quiescent cells but not in proliferating cells after irradiation. Moreover, quiescent cells expressing EGFR underwent increased radiation-induced clonogenic death compared with both proliferating CHO cells expressing EGFR and quiescent wild-type CHO cells. Our data show that radiation-induced enhancement of cell death in quiescent cells involves activation of the EGFR and extracellular signal-regulated kinase pathways. Furthermore, they suggest that EGFR inhibitors may protect quiescent tumor cells, whereas radiosensitization of proliferating cells may be caused by downstream effects such as cell cycle redistribution. These findings emphasize the need for careful scheduling of treatment with the combination of EGFR inhibitors and radiation and suggest that EGFR inhibitors might best be given after radiation in order to optimize clinical outcome.

Molecular Targets for Tumor Radiosensitization

Molecular Targets for Tumor Radiosensitization

The von Hippel-Lindau protein sensitizes renal carcinoma cells to apoptotic stimuli through stabilization of BIMEL

von Hippel-Lindau (VHL) disease is caused by germ-line mutations in the VHL tumor suppressor gene and is the most common cause of inherited renal cell carcinoma (RCC). Mutations in the VHL gene also occur in a large majority of sporadic cases of clear-cell RCC, which have high intrinsic resistance to chemotherapy and radiotherapy. Here we show that VHL-deficient RCC cells express lower levels of the pro-apoptotic Bcl-2 family protein BIMEL and are more resistant to etoposide and UV radiation induced death compared to the same cells stably expressing the wild type VHL protein (pVHL). Re-introducing pVHL into VHL-null cells increased the half-life of BIMEL protein without affecting its mRNA expression, and over-expressing pVHL inhibited BIMEL polyubiquitination. Suppressing pVHL expression with RNA interference resulted in a decrease in BIMEL protein and a corresponding decrease in the sensitivity of RCC cells to apoptotic stimuli. Directly inhibiting BIMEL expression in pVHL-expressing RCC cells caused a similar decrease in cell death. These results demonstrate that pVHL acts to promote BIMEL protein stability in RCC cells, and that destabilization of BIMEL in the absence of pVHL contributes to the increased resistance of VHL-null RCC cells to certain apoptotic stimuli.

Combined action of celecoxib and ionizing radiation in prostate cancer cells is independent of pro-apoptotic Bax

Background and purpose The cyclooxygenase-2-inhibitor celecoxib has been shown to inhibit cell growth and to reduce prostatic intraepithelial neoplasia in mice. The drug was suggested to increase efficacy of ionizing radiation. However, extent and mechanisms of the suggested benefit of celecoxib on the radiation response are still unclear. The aim of the present study was to analyze cytotoxic efficacy of celecoxib in combination with irradiation on human prostate cancer cell lines and to define the importance of pro-apoptotic Bax in this process. Materials and methods Induction of apoptosis and global and clonogenic cell survival upon irradation- (2–10 Gy), celecoxib- (10–75 μM) or combined treatment were evaluated in prostate cancer cells by fluorescence microscopy, WST-1 assay and standard colony formation assays. Results Celecoxib <25 μM caused morphological changes and growth inhibition without substantial apoptosis or radiosensitization in terms of decreased clonogenic cell survival. In contrast, celecoxib ⩾25 μM increased radiation-induced cell death and clonogenic kill. While radiation-induced clonogenic death was increased in the presence of Bax, effects of celecoxib or combined treatment were Bax independent. Conclusions Our findings reveal Bax-independent beneficial effects of celecoxib on radiation-induced apoptosis and eradication of clonogenic prostate cancer cells in vitro providing a rationale for clinical evaluation of high-dose celecoxib in combination with irradiation in prostate cancer patients.

Gefitinib (Iressa) Potentiates the Effect of Ionizing Radiation in Thyroid Cancer Cell Lines

To determine whether inactivation of epidermal growth factor receptor (EGFR) kinase activity will sensitize thyroid cancer cell lines to ionizing radiation-induced death. Established human thyroid cancer cells lines were studied. Colony formation assay was used to determine the effect of Gefitinib, a small molecule inhibitor of EGFR, on anaplastic (ARO) and follicular (WRO) thyroid cancer cell lines. In addition, colony formation assay was used to determine the effect of ionizing radiation in the presence or absence of Gefitinib. EGFR protein expression on the cell lines and inactivation of EGFR kinase by Gefitinib was analyzed by Western blot. Immunohistochemistry was performed on archived thyroid cancer tissue to demonstrate expression of EGFR. Incubation with Gefitinib caused decreased phosphorylation of EGFR protein in established thyroid cancer cell lines as measured by Western blot. Inhibition of EGFR kinase activity by Gefitinib resulted in a dose-dependent decrease in colony formation in both ARO and WRO thyroid cancer cell lines. Addition of Gefitinib in combination with ionizing radiation reduced cell proliferation in ARO (P = .0084) and WRO (P = .0252) as measured by colony formation assay. Inactivation of the EGFR kinase by Gefitinib potentiates the ionizing radiation-induced inhibition of cell proliferation in thyroid cancer cell lines. Use of this combination treatment of Gefitinib and ionizing radiation may be a promising therapy for anaplastic thyroid and metastatic follicular thyroid cancer and should be extended into animal models.

Mechanisms of radiation-induced brain toxicity and implications for future clinical trials

Radiation therapy is widely used in the treatment of primary malignant brain tumors and metastatic tumors of the brain with either curative or palliative intent. The limitation of cancer radiation therapy does not derive from the inability to ablate tumor, but rather to do so without excessively damaging the patient. Among the varieties of radiation-induced brain toxicities, it is the late delayed effects that lead to severe and irreversible neurological consequences. Following radiation exposure, late delayed effects within the CNS have been attributable to both parenchymal and vascular damage involving oligodendrocytes, neural progenitors, and endothelial cells. These reflect a dynamic process involving radiation-induced death of target cells and subsequent secondary reactive neuroinflammatory processes that are believed to lead to selective cell loss, tissue damage, and functional deficits. The progressive, late delayed damage to the brain after high-dose radiation is thought to be caused by radiation-induced long-lived free radicals, reactive oxygen species, and pro-inflammatory cytokines. Experimental studies suggest that radiation-induced brain injury can be successfully mitigated and treated with several well established drugs in wide clinical use which exert their effects by blocking pro-inflammatory cytokines and reactive oxygen species. This review highlights preclinical and early clinical data that are translatable for future clinical trials.