Antioxidant/antifibrotic agents Region Radiation dose/animals Dose Effects Reference AEOL 10150 (catalytic SOD mimic) Lung 28 Gy/rats 10-30 mg/kg/day, for 10 weeks Inhibits TGF-β signaling [291 ] Alpha-lipoic acid Small intestine 15 Gy/mice 100 mg/kg, 3 days before radiation Reduces inflammation and cell death and reduces p-NF-κ B, MMP9, and MAPK signaling and facilitates regeneration of vitamins C and E and elevates glutathione levels [292 ] [293 ] Thyroid 18 Gy/rats 100 mg/kg, 24 h before radiation Inhibits TGF-β signaling [115 ] Salivary gland 18 Gy/rats 100 mg/kg, 24 h before irradiation Reduces oxidative stress by inhibiting gp91 mRNA expression [294 ] Amifostine (WR-2721) Head and neck 20–70 Gy/humans 200 mg/m2 to 400 mg/m2 Thiol compound and free radical scavenger; reduces oxidative radicals and prevents xerostomia (dry mouth) postradiation. [295 , 296 ] Heart 22.5 Gy/rats 160 mg/kg, 15 minutes before radiation Reduces cardiac damage [297 ] Heart 18 Gy/mice 200 mg/kg, 30 minutes before radiation Prevents vasculitis and vascular injury [298 ] Kidney 15 Gy 200 mg/kg, 30 minutes before radiation Prevents glomerular and tubular changes and interstitial fibrotic lesions postradiation [299 , 300 ] Atorvastatin Kidney 2 Gy/mice 50 mg/kg/day for 1 week Reduces the levels of oxidative stress biomarkers [301 ] CpG oligodeoxynucleotide Lung 15 Gy/mice 50 μ g CpG-ODN Prevents radiation-induced pulmonary fibrosis by shifting the imbalance of Th1 and Th2 responses [302 ] Curcumin Lung 18 Gy/rats 200 mg/kg/day, 1 week before radiation Boosts antioxidant defenses by increasing HO-1, prevents COX-2 upregulation, and inhibits proinflammatory cytokines and NF-κ B signaling [303 ] Lung 13.5 Gy/mice 1% or 5% (w /w ) Prevents radiation-induced pulmonary fibrosis and reduces LPS-induced TNF-α production [304 ] Erdosteine Whole body/kidney 5 Gy/rats 100 mg/kg/day, 1 week before irradiation by gastric tube Inhibits production of proinflammatory cytokines TNF-α , IL-1, IFNγ , and IL-6 [305 ] Eukarion-189 (catalytic SOD catalase mimic) Lung 10 to 20.5 Gy/rats 30 mg/kg, 30 minutes before radiation Inhibits TGF-β signaling [306 ] Eukarion-207 (catalytic SOD catalase mimic) Lung 12 Gy/rats 8 mg/kg/day Reduces oxidative damage, TGF-β , and NF-κ B signaling and activated macrophages [307 ] Flaxseed Lung 13.5 Gy/mice 10% (w /w ) Reduces expression of lung injury biomarkers (Bax, p21, and TGF-β ) and contains omega-3 fatty acids and lignans with antioxidant properties [308 ] Follistatin Hindlimb 35 Gy/mice 4 μ g, 24 hours before, 2 days after radiation, and then 3/week over 6 months Inhibits TGF-β signaling [285 ] GC4401 Whole body/liver 2 mg/kg before every fraction Protects the liver in Sirt3−/− animals from radiation-induced injury [309 ] GC4419 Oral cavity 60 to 72 Gy/humans 15 to 112 mg/day, 60 min before radiation for 3 to 7 weeks Reduces the frequency and duration of oral mucositis [310 ] Genistein (isoflavone) Lung 12 Gy/rats 50 mg/kg/day Reduces oxidative damage, TGF-β , and NF-κ B signaling and activated macrophages and fibrosis [307 ] Ginger extract Kidney 2, 4, and 8 Gy/rats 50 mg/kg/day for 10 days Alleviates functional and structural alterations in the kidney due to antioxidant and anti-inflammatory effects [311 ] Gingko biloba Whole body 8 Gy/rats 50 mg/kg/day, 15-day pretreatment Attenuates irradiation-induced oxidative organ injury, by preventing an increase in LDH and TNF-alpha levels [312 ] Eye 5 Gy/rats 40 mg/kg/day, 3 days pretreatment and up to 7 days postradiation Prevents increase in xanthine oxidase (XO) activity postradiation [313 ] Whole body 6 Gy/rats 50 and 100 mg/kg/day for 7 days Corrects the metabolic disturbances induced in the brain by lowering dopamine, calcium, and zinc contents while increasing iron content and restores the activities of lactate dehydrogenase and cholinesterase enzymes [314 ] GTS-21 (α 7-nAChR agonist) Lung 12 Gy/mice 4 mg/kg/day Reduces TNF-α , IL-1β , and IL-6 production in serum via inhibition of NF-κ B and downregulates TLR-4 and HMGB1 expression in the lungs and reduces ROS levels and HIF-1α expression along with inhibition of NOX1 and NOX2 expression [315 ] Hesperidin Heart 18 Gy/rats 100 mg/kg/day for 7 days Decreases inflammation, fibrosis, mast cell and macrophage numbers, and myocyte necrosis after radiation [316 ] JP4-039 (TEMPOL) Skin/leg 35 Gy/mice 50 μ L of formulation, 0.5, 24, and 48 h after radiation Reduces radiation-induced skin damage [317 ] KL4 surfactant (21-amino acid peptide) Lung 13.5 Gy/mice 120 mg/kg twice daily Reduces lung inflammation and oxidative stress [318 ] Matrine (alkaloid) Whole body 6-7 Gy/rats 30, 10, and 3 mg/kg/day, 3 days before or after radiation Reduces radiation-induced damage by altering 21 pathways [319 ] Melatonin Lung 18 Gy/rats 100 mg/kg once 30 minutes before radiation Reduces lipid peroxidation product malondialdehyde [320 ] MnTnHex-2-PyP (catalytic SOD mimic) Lung 28 Gy/rats 0.05 mg/kg/day for 2 weeks, 2 h postradiation Decreases HIF-1alpha, TGF-β , and VEGF A expression after radiation [321 ] Lung 28 Gy/rhesus monkeys 0.05 mg/kg twice daily for 2 months Prevents radiation injury in the lungs [322 ] MnTE-2-PyP Or AEOL 10113 (catalytic SOD mimic) Prostate 10 Gy/mice 6 mg/kg/day, day 1 to 16 Inhibits TGF-β signaling and protects against decreases in RBC counts, hemoglobin, and hematocrit [323 ] Pelvic region 20-30 Gy/rats 5 mg/kg/week, 1 h before radiation Ameliorates both acute and chronic radiation proctitis [324 ] Pelvic region 37.5 Gy/mice 10 mg/kg/week, 24 h before radiation; for the first two weeks, 3 times/week at a dose of 5 mg/kg Reduces collagen deposition, inflammation, senescence, and fibroblast to myofibroblast differentiation and upregulates NQO1 expression [286 ] Lung 28 Gy/rats 6 mg/kg/day, 15 min before radiation Inhibits TGF-β signaling [325 ] Lung 28 Gy/rats 6 mg/kg/day for 10 weeks Decreases HIF-1alpha, TGF-β , and VEGF A expression after radiation [326 ] MnTnBuOE-2-PyP5 or BMX-001 (catalytic SOD mimic) Brain 5 Gy/mice 1.5 mg/kg, twice daily, for 14 days Protects hippocampal neurogenesis [288 ] Brain 8 Gy/mice 1.6 mg/kg, twice daily, 24 h before radiation Protects the brain from negative effects of cranial irradiation [327 , 328 ] Colon 2 Gy/mice 0.25 μ M every 3 days, for in vitro studies Prevents activation and increase in cell size of fibroblast cells from the colon [287 ] N-Acetyl cysteine (NAC) Whole body 18 Gy/mice 500 mg/kg/day, 3 days before and up to 3 days postradiation Protects the lung and red blood cells from glutathione depletion following irradiation [329 ] Whole body 6 Gy/rats 1000 mg/kg, 15 min before radiation Protects rat femoral bone marrow cells from radiation-induced genotoxicity and cytotoxicity [330 ] Abdomen 10 Gy/rats 300 mg/kg/day Alleviates the negative effects of radiotherapy on incisional wound healing by means of reducing oxidative stress markers [331 ] Abdomen 20 Gy/mice 300 mg/kg/day, for 7 days Prevents gastrointestinal injury, damage to bone marrow stromal cells, and radiation-induced acute death [326 ] Plasminogen activator inhibitor-1 (PAI-1) truncated Lung 30 Gy/mice 5.4 μ g/kg/day for 18 weeks beginning 2 days before radiation Prevents RIF with increased fibrin metabolism, enhanced matrix metalloproteinase-3 expression, and reduced senescence in type 2 pneumocytes [332 ] Pirfenidone Lung 16 Gy/mice 300 mg/kg/day for four weeks Inhibits TGF-β signaling [333 ] Intestine 20 Gy/mice 200 and 400 mg/kg/day for 12 weeks [334 ] Head and neck 60-72 Gy/humans 800 mg three times/day — [335 ] Podophyllotoxin and rutin combination (G-003M) Lung 11 Gy/mice 5 mg/kg once Reduces radiation-induced oxidative and inflammatory stress [336 ] Polydatin Lung 15 Gy/mice 100 mg/kg/day Exerts anti-inflammation and antioxidative properties through Nrf2 signaling and Sirt3 upregulation [213 ] Quercetin Intestine 13 Gy/mice 100 mg/kg/day for 6 days before and after radiation Inhibits TGF-β signaling [337 ] Skin/hind leg 35 Gy and 10 Gy/mice Quercetin-formulated chow (1% by weight) [338 ] Resveratrol Intestine 7 Gy/mice 40 mg/kg/day, 1-day pretreatment and up to day 5 Prevents intestine damage via the activation of Sirt1, improves intestinal morphology, decreases apoptosis of crypt cells, maintained cell regeneration, ameliorated SOD2 expression and activity, regulates Sirt1, and acetylated p53 expression that is perturbed by irradiation [339 ] Whole body 3 Gy/mice 100 mg/kg/day, 2 days pretreatment and up to 30 days Reduces radiation-induced chromosome aberration frequencies [340 ] Salivary gland 15 Gy/mice 20 mg/kg/day Inhibits TGF-β signaling and protects the salivary glands against the negative effects of irradiation [341 ] Ovary 21 Gy/rats 25 mg/kg/day for 2 weeks Counteracts the effect of radiation and upregulates the gene expression of PPAR-γ and Sirt1, leading to inhibition of NF-κ B-provoked inflammatory cytokines [191 , 342 ] Whole body/hematopoietic stem cell 6 Gy/mice 20 mg/kg/day for 7 days before and then up to 30 days postradiation Protects from radiation-induced injury, in part, via activation of Sirt1 [343 ] Skin 35 Gy/mice 1% by weight Inhibits TGF-β signaling [338 ] Lung 13 Gy/mice 100 mg/kg/day for 7 days Prevents lung injury by reducing inflammation and fibrosis [344 ] rhNRG-1β Heart 20 Gy/rats 15 μ g/kg, 3 days before and 7 days after radiation Prevents fibrosis and preserves cardiac function via the ErbB2-ERK-Sirt1 signaling pathway [345 ] Silibinin Breast 46.8-50.4 Gy/humans 400 IU for 6 months Vitamin E may be clinically useful in preventing fibrosis after radiation in high-risk patients [346 ] SOD gliadin Hind leg/skin 25 Gy/mice 10000 units/kg/day for 8 days Reduces dermal thickness and fibrosis after irradiation [347 ] Soy isoflavones Prostate 73.8 to 77.5 Gy/humans 200 mg tablet containing 50 mg soy isoflavones (genistein, daidzein, and glycitein at a ratio of 1.1 : 1 : 0.2) Reduces the urinary, intestinal, and sexual adverse effects in patients with prostate cancer receiving radiation therapy [348 ] Lung 12 Gy/mice 50 mg/kg/day, 3 days before and up to 4 months after radiation Mitigates inflammatory infiltrates and radiation-induced lung injury [349 ] Lung 10 Gy 250 mg/kg/day, 3-day pretreatment Inhibits the infiltration and activation of macrophages and neutrophils induced by radiation in the lungs [350 ] Lung 12 Gy/mice 250 mg/kg/day, 3-day pretreatment and up to 4 months after radiation Inhibits the infiltration and activation of macrophages and neutrophils induced by radiation in the lungs [349 ] Taurine Lung 14 Gy/mice 32 mg/kg/day Inhibits TGF-β signaling; taurine essential amino acid is involved in osmoregulation, antioxidation, detoxification, membrane stabilization, neuromodulation, cardiac function, and central nervous system development [351 ] Brain 6 Gy/rats 2 oral doses of 500 mg/kg/day for 2 weeks Taurine has antioxidant, anti-inflammatory, and antiapoptotic effects [352 ] Sperm cells 8 Gy/mice spermatocytes (GC-2 cells) 40 mM Activates Nrf2/HO-1 signaling [353 ] Vitamin E Lung & heart 20 Gy/rats 2.5% of diet 2 weeks before radiation or 150 mg injected 4 h before radiation Protects lungs and heart tissues from radiation damage [354 ] L4ung 14 Gy/rats 1.1 mg/day dissolved in 0.1 mL olive oil injected Protects against the development of RIF [355 ] Whole body 9.2 Gy/mice 50 mg/kg 24 h before radiation Protects against acute radiation syndrome [356 ] SKI2162 Hind limb 22 Gy/mice 10 mg/kg/day, 5 times/week An inhibitor of the TGF-β type I receptor (ALK5) and inhibits radiation-induced fibrosis [357 ] GV1001 (hTERT peptide fragment) Skin 6 Gy/mice 1 mg/kg/day and 5 mg/kg/day for 4 weeks Suppresses TGF-β signaling [358 ] XH-103 Intestine 11 Gy/mice 200 mg/kg, 1 before radiation Prevents damage to the intestinal crypt-villus structure [359 ]
