Review on Natural Bioactive Products as Radioprotective Therapeutics: Present and Past Perspective

Seema      Raj; Romila      Manchanda; Meena      Bhandari; Md.   Sabir   Alam
Abstract

Among conventional treatment methodologies, surgery, hyperthermia, radiation, and chemotherapy have become integral components of treatment for most cancers. Radiation therapy in the treatment of many malignancies is always the better choice over surgery and chemotherapy. Ionizing radiation produced as a consequence of using these radiations has always been a concern in these treatment methods. Synthetic radio-protectors with their inherent limitations are being used to date to reduce the mortality of these radiations; still, it compromises the clinical efficacy of these administrations. Hence, investigations for alternative methods, including natural resources such as plant and fruit extracts, are being explored to treat radiation-mediated ailments. The present review article endeavors to provide a comprehensive, updated, and chronological account of these promising plants and fruit extracts and their bioactive principles as radio-protectors. We present the merits and demerits of radiation therapy and cell stress generation of reactive oxygen species (ROS) associated with radiation need and availability of radio-protectors. Finally, we discuss green-based bioactive compounds that have radioprotective properties.
Keywords: Plant extract, radiation therapy, radioprotectors, ionization radiations, chemotherapy, cancer.
Graphical Abstract

[1] 
Alteri, R.; Bertaut, T.; Brooks, D.; Chambers, W.; Chang, E.; Chen, M.S. Cancer Facts and Figures is an annual publication of the Ameri-can Cancer Society.,  Atlanta, Georgia, 2016, 23.
[2] 
Bray, F.; Møller, B. Predicting the future burden of cancer. Nat. Rev. Cancer,  2006, 6(1), 63-74.
[http://dx.doi.org/10.1038/nrc1781] [PMID: 16372017] 
[3] 
Nawaz, F.; Alam, O.; Perwez, A.; Rizvi, M.A.; Naim, M.J.; Siddiqui, N.; Pottoo, F.H.; Jha, M. 3′-(4-(Benzyloxy)phenyl)-1′-phenyl-5-(heteroaryl/aryl)-3,4-dihydro-1‘H,2H-[3,4’-bipyrazole]-2-carboxamides as EGFR kinase inhibitors: Synthesis, anticancer evaluation, and molecular docking studies. Arch. Pharm. (Weinheim),  2020, 353(4), e1900262.
[http://dx.doi.org/10.1002/ardp.201900262] [PMID: 32003485] 
[4] 
El Rayes, S.M.; Aboelmagd, A.; Gomaa, M.S.; Fathalla, W.; Ali, I.A.; Pottoo, F.H.; Khan, F.A. Newly synthesized 3-(4-chloro-phenyl)-3-hydroxy-2, 2-dimethyl-propionic acid methyl ester derivatives selectively inhibit the proliferation of colon cancer cells. RSC Advances,  2020, 10(15), 8825-8841.
[http://dx.doi.org/10.1039/C9RA10950A] 
[5] 
El Rayes, S.M.; Aboelmagd, A.; Gomaa, M.S.; Ali, I.A.I.; Fathalla, W.; Pottoo, F.H.; Khan, F.A. Convenient synthesis and anticancer activ-ity of methyl 2-[3-(3-phenyl-quinoxalin-2-ylsulfanyl)propanamido]alkanoates and n-alkyl 3-((3-phenyl-quinoxalin-2-yl)sulfanyl)propanamides. ACS Omega,  2019, 4(20), 18555-18566.
[http://dx.doi.org/10.1021/acsomega.9b02320] [PMID: 31737814] 
[6] 
Gangshi, W.; Lichan, C.; Baofa, Yu.; Lucas, Z.; Ningzhi, Xu.; Joshua, L. Learning about the importance of mutation prevention from cura-blecancers and benign tumors. J. Cancer,  2016, 7(4), 436-445.
[http://dx.doi.org/10.7150/jca.13832] [PMID: 26918057] 
[7] 
Shafi, S.; Khan, S.; Hoda, F.; Fayaz, F.; Singh, A.; Khan, M.A.; Ali, R.; Pottoo, F.H.; Tariq, S.; Najmi, A.K. Decoding novel mechanisms and emerging therapeutic strategies in breast cancer resistance. Curr. Drug Metab.,  2020, 21(3), 199-210.
[http://dx.doi.org/10.2174/1389200221666200303124946] [PMID: 32124694] 
[8] 
Vilaboa, N.; Sáez-Gutierrez, B.; Lambea, J.; Tres, A.; Valladares, M.; González-Fernández, A. Assessment of the evolution of cancer treat-ment therapies manuel. Cancers (Basel),  2011, 3, 3279-3330.
[9] 
Pearson, O.H.; Eliel, L.P.; Rawson, R.W.; Dobriner, K.; Rhoads, C.P. ACTH- and cortisone-induced regression of lymphoid tumors in man: A preliminary report. Cancer,  1949, 2, 943-945.
[http://dx.doi.org/10.1002/1097-0142(194911)2:6<943:AID-CNCR2820020602>3.0.CO;2-P] [PMID: 15395192] 
[10] 
Li, M.C.; Hertz, R.; Bergenstal, D.M. Therapy of choriocarcinoma and related trophoblastic tumors with folic acid and purine antagonists. N. Engl. J. Med.,  1958, 259(2), 66-74.
[http://dx.doi.org/10.1056/NEJM195807102590204] [PMID: 13566422] 
[11] 
Johnson, I.S.; Armstrong, J.G.; Gorman, M.; Burnett, J.P., Jr The vinca alkaloids: A new class of oncolytic agents. Cancer Res.,  1963, 23, 1390-1427.
[PMID: 14070392] 
[12] 
Brunner, K.W.; Young, C.W. A methylhydrazine derivative in Hodgkin’s disease and other malignant neoplasms. Therapeutic and toxic effects studied in 51 patients. Ann. Intern. Med.,  1965, 63, 69-86.
[http://dx.doi.org/10.7326/0003-4819-63-1-69] [PMID: 14305970] 
[13] 
DeVita, V.T.; Serpick, A.; Carbone, P.P. Preliminary clinical studies with ibenzmethyzin. Clin. Pharmacol. Ther.,  1966, 7(4), 542-546.
[http://dx.doi.org/10.1002/cpt196674542] [PMID: 5939977] 
[14] 
Singh, A.; Shafi, S.; Upadhyay, T.; Najmi, A.K.; Kohli, K.; Pottoo, F.H. Insights into nanotherapeutic strategies as an impending approach for liver cancer treatment. Curr. Top. Med. Chem.,  2020, 20(20), 1839-1854.
[http://dx.doi.org/10.2174/1568026620666200624161801] [PMID: 32579503] 
[15] 
Mumtaz, S.M.; Bhardwaj, G.; Goswami, S.; Tonk, R.K.; Goyal, R.K.; Pottoo, F.H. Management of glioblastoma multiforme by phytochem-icals: Applications of nanoparticle based targeted drug delivery system. Curr. Drug Targets,  2021, 22(4), 429-442.
[PMID: 32718288] 
[16] 
Pottoo, F.H.; Javed, N.; Rahman, J.; Abu-Izneid, T.; Khan, F.A. Insights into nanotherapeutic strategies as an impending approach for liver cancer treatment. Curr. Top. Med. Chem.,  2020, 20(20), 1839-1854.
[17] 
Hall, E.J. Intensity-modulated radiation therapy, protons, and the risk of second cancers. Int. J. Radiat. Oncol. Biol. Phys.,  2006, 65(1), 1-7.
[http://dx.doi.org/10.1016/j.ijrobp.2006.01.027] [PMID: 16618572] 
[18] 
Lawrence, T.S.; Ten Haken, R.K.; Giaccia, A. Principles of radiation oncology. In: Cancer: Principles and Practice of Oncology,  8th ed; Lippincott Williams and Wilkins, 2008.
[19] 
Seiwert, T.Y.; Salama, J.K.; Vokes, E.E. The chemoradiation paradigm in head and neck cancer. Nat. Clin. Pract. Oncol.,  2007, 4(3), 156-171.
[http://dx.doi.org/10.1038/ncponc0750] [PMID: 17327856] 
[20] 
Oehler, C.; Dickinson, D.J.; Broggini-Tenzer, A.; Hofstetter, B.; Hollenstein, A.; Riesterer, O.; Vuong, V.; Pruschy, M. Current concepts for the combined treatment modality of ionizing radiation with anticancer agents. Curr. Pharm. Des.,  2007, 13(5), 519-535.
[http://dx.doi.org/10.2174/138161207780162935] [PMID: 17348847] 
[21] 
Early Breast Cancer Trialists’ Collaborative Group. Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. An overview of 61 randomized trials among 28,896 women. N. Engl. J. Med.,  1988, 319(26), 1681-1692.
[http://dx.doi.org/10.1056/NEJM198812293192601] [PMID: 3205265] 
[22] 
Murphy, M.J.; Li, T. Introduction. image-guided and adaptive radiation therapy; Lippincott Williams & Wilkins: Philadelphia, PA, USA, 2010, pp. 3-15.
[23] 
Curry, H.A.; Curran, W.J. Chemoradiation strategies for patients with malignant gliomas.Chemoradiation in Cancer Therapy; Choy, H., Ed.; Humana Press Inc.: Totowa, NJ, 2003, p. 129.
[24] 
Choy, H. Taxanes in combined modality therapy for solid tumors. Crit. Rev. Oncol. Hematol.,  2001, 37(3), 237-247.
[http://dx.doi.org/10.1016/S1040-8428(00)00112-8] [PMID: 11248579] 
[25] 
Amorino, G.P.; Mohr, P.J.; Hercules, S.K.; Pyo, H.; Choy, H. Combined effects of the orally active cisplatin analog, JM216, and radiation in antitumor therapy. Cancer Chemother. Pharmacol.,  2000, 46(5), 423-426.
[http://dx.doi.org/10.1007/s002800000169] [PMID: 11127948] 
[26] 
Moding, E.J.; Kastan, M.B.; Kirsch, D.G. Strategies for optimizing the response of cancer and normal tissues to radiation. Nat. Rev. Drug Discov.,  2013, 12(7), 526-542.
[http://dx.doi.org/10.1038/nrd4003] [PMID: 23812271] 
[27] 
Oh, J.Y.; Fernando, I.P.S.; Jeon, Y.J. Potential applications of radioprotective phytochemicals from marine algae. Algae,  2016, 31, 403-414.
[http://dx.doi.org/10.4490/algae.2016.31.12.1] 
[28] 
Singh, V.K.; Newman, V.L.; Romaine, P.L.; Hauer-Jensen, M.; Pollard, H.B. Use of biomarkers for assessing radiation injury and efficacy of countermeasures. Expert Rev. Mol. Diagn.,  2016, 16(1), 65-81.
[http://dx.doi.org/10.1586/14737159.2016.1121102] [PMID: 26568096] 
[29] 
Tulard, A.; Hoffschir, F.; de Boisferon, F.H.; Luccioni, C.; Bravard, A. Persistent oxidative stress after ionizing radiation is involved in inherited radiosensitivity. Free Radic. Biol. Med.,  2003, 35(1), 68-77.
[http://dx.doi.org/10.1016/S0891-5849(03)00243-0] [PMID: 12826257] 
[30] 
Boveris, A.; Chance, B. The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem. J.,  1973, 134(3), 707-716.
[http://dx.doi.org/10.1042/bj1340707] [PMID: 4749271] 
[31] 
Boveris, A.; Cadenas, E.; Stoppani, A.O. Role of ubiquinone in the mitochondrial generation of hydrogen peroxide. Biochem. J.,  1976, 156(2), 435-444.
[http://dx.doi.org/10.1042/bj1560435] [PMID: 182149] 
[32] 
Kam, W.W.; Banati, R.B. Effects of ionizing radiation on mitochondria. Free Radic. Biol. Med.,  2013, 65, 607-619.
[http://dx.doi.org/10.1016/j.freeradbiomed.2013.07.024] [PMID: 23892359] 
[33] 
Jiang, P.S.; Tsai, H.Y.; Drake, P.; Wang, F.N.; Chiang, C.S. Gadolinium-doped iron oxide nanoparticles induced magnetic field hyperther-mia combined with radiotherapy increases tumour response by vascular disruption and improved oxygenation. Int. J. Hyperthermia,  2017, 33(7), 770-778.
[http://dx.doi.org/10.1080/02656736.2017.1308019] [PMID: 28540811] 
[34] 
Wanyeon, K.; Sungmin, L.; Danbi, S.; Dain, K.; Kyeongmin, K. EunGi, K.; JiHoon, K.; Ki, M.S.; HyeSook, Y.; BuHyun, Y. Cellular stress responses in radiotherapy. Cells,  2019, 8, 1105.
[35] 
Reisz, J.A.; Bansal, N.; Qian, J.; Zhao, W.; Furdui, C.M. Effects of ionizing radiation on biological molecules--mechanisms of damage and emerging methods of detection. Antioxid. Redox Signal.,  2014, 21(2), 260-292.
[http://dx.doi.org/10.1089/ars.2013.5489] [PMID: 24382094] 
[36] 
Begum, N.; Prasad, N.R.; Thayalan, K. Apigenin protects gamma radiation induced oxidative stress, haematological changes and animal survival in whole body irradiated Swiss albino mice. Int. J. Nutr. Pharmacol. Neurol.,  2012, 2, 45-52.
[http://dx.doi.org/10.4103/2231-0738.93134] 
[37] 
López, M.; Martín, M. Medical management of the acute radiation syndrome. Rep. Pract. Oncol. Radiother.,  2011, 16(4), 138-146.
[http://dx.doi.org/10.1016/j.rpor.2011.05.001] [PMID: 24376971] 
[38] 
Rodgerson, D.O.; Reidenberg, B.E.; Harris, A.G.; Pecora, A.L. Potential for a pluripotent adult stem cell treatment for acute radiation sick-ness. World J. Exp. Med.,  2012, 2(3), 37-44.
[http://dx.doi.org/10.5493/wjem.v2.i3.37] [PMID: 24520532] 
[39] 
Green, D.E.; Rubin, C.T. Consequences of irradiation on bone and marrow phenotypes, and its relation to disruption of hematopoietic precursors. Bone,  2014, 63, 87-94.
[http://dx.doi.org/10.1016/j.bone.2014.02.018] [PMID: 24607941] 
[40] 
Singariya, S.; Songara, V.; Agarwal, M.; Chakrawarti, A. Radioprotective potential of Aloe vera against radiation and cadmium mediated alterations in differential leucocyte count of Swiss albino mice. Int. J. Adv. Res. (Indore),  2015, 3, 1493-1503.
[41] 
Xue, X.L.; Han, X.D.; Li, Y.; Chu, X.F.; Miao, W.M.; Zhang, J.L.; Fan, S.J. Astaxanthin attenuates total body irradiation-induced hemato-poietic system injury in mice via inhibition of oxidative stress and apoptosis. Stem Cell Res. Ther.,  2017, 8(1), 7.
[http://dx.doi.org/10.1186/s13287-016-0464-3] [PMID: 28115023] 
[42] 
Pernot, E.; Hall, J.; Baatout, S.; Benotmane, M.A.; Blanchardon, E.; Bouffler, S.; El Saghire, H.; Gomolka, M.; Guertler, A.; Harms-Ringdahl, M.; Jeggo, P.; Kreuzer, M.; Laurier, D.; Lindholm, C.; Mkacher, R.; Quintens, R.; Rothkamm, K.; Sabatier, L.; Tapio, S.; de Vathaire, F.; Cardis, E. Ionizing radiation biomarkers for potential use in epidemiological studies. Mutat. Res.,  2012, 751(2), 258-286.
[http://dx.doi.org/10.1016/j.mrrev.2012.05.003] [PMID: 22677531] 
[43] 
Nada, A.S.; Hawas, A.M.; Abd Elmageed, Z.Y. Protective value of Aloe vera extract against gamma-irradiation induced some biochemical disorders in rats. J. Radiat. Res. Appl. Sci.,  2013, 6, 31-37.
[http://dx.doi.org/10.1016/j.jrras.2013.10.003] 
[44] 
Hosseinimehr, S.J.; Zakaryaee, V.; Froughizadeh, M. Oral oxymetholone reduces mortality induced by gamma irradiation in mice through stimulation of hematopoietic cells. Mol. Cell. Biochem.,  2006, 287(1-2), 193-199.
[http://dx.doi.org/10.1007/s11010-005-9111-5] [PMID: 16532255] 
[45] 
Bhandari, P.R. A review of radioprotective plants. Inte. J. Green Pharm.,  2013, 7, 90-101.
[http://dx.doi.org/10.4103/0973-8258.116379] 
[46] 
Dai, Y.; Grant, S. Targeting multiple arms of the apoptotic regulatory machinery. Cancer Res.,  2007, 67(7), 2908-2911.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-0082] [PMID: 17409392] 
[47] 
Qiu, W.; Carson-Walter, E.B.; Liu, H.; Epperly, M.; Greenberger, J.S.; Zambetti, G.P.; Zhang, L.; Yu, J. PUMA regulates intestinal progeni-tor cell radiosensitivity and gastrointestinal syndrome. Cell Stem Cell,  2008, 2(6), 576-583.
[http://dx.doi.org/10.1016/j.stem.2008.03.009] [PMID: 18522850] 
[48] 
Greenberger, J.S. Radioprotection. In Vivo,  2009, 23(2), 323-336.
[PMID: 19414422] 
[49] 
C., Jagetia G. Radioprotective potential of plants and herbs against the effects of ionizing radiation. J. Clin. Biochem. Nutr.,  2007, 40(2), 74-81.
[http://dx.doi.org/10.3164/jcbn.40.74] [PMID: 18188408] 
[50] 
Kumar, S.; Tiku, A.B. Biochemical and molecular mechanisms of radioprotective effects of naringenin, a phytochemical from citrus fruits. J. Agric. Food Chem.,  2016, 64(8), 1676-1685.
[http://dx.doi.org/10.1021/acs.jafc.5b05067] [PMID: 26881453] 
[51] 
Ruba, T.; Tamilselvi, R. Radiosensitizers and radioprotectors for effective radiation therapy– a review. Asian J. Appl. Sci. Techno.,  2018, 2(1), 77-86.
[52] 
Kumar, S.; Meena, R.; Rajamani, P. Fabrication of BSA-green tea polyphenols-chitosan nanoparticles and their role in radioprotection: a molecular and biochemical approach. J. Agric. Food Chem.,  2016, 64(30), 6024-6034.
[http://dx.doi.org/10.1021/acs.jafc.6b02068] [PMID: 27389300] 
[53] 
Araújo, M.C.; Dias, F.L.; Takahashi, C.S. Potentiation by turmeric and curcumin of gamma-radiation-induced chromosome aberrations in Chinese hamster ovary cells. Teratog. Carcinog. Mutagen.,  1999, 19(1), 9-18.
[http://dx.doi.org/10.1002/(SICI)1520-6866(1999)19:1<9:AID-TCM2>3.0.CO;2-H] [PMID: 10321406] 
[54] 
Agbor, G.A.; Vinson, J.A.; Oben, J.E.; Ngogang, J.Y. Comparative analysis of the in vitro antioxidant activity of white and black pepper. Nutr. Res.,  2006, 26(12), 659-663.
[http://dx.doi.org/10.1016/j.nutres.2006.09.019] 
[55] 
Weiss, J.F.; Landauer, M.R. Protection against ionizing radiation by antioxidant nutrients and phytochemicals. Toxicology,  2003, 189(1-2), 1-20.
[http://dx.doi.org/10.1016/S0300-483X(03)00149-5] [PMID: 12821279] 
[56] 
Harapanhalli, R.S.; Narra, V.R.; Yaghmai, V.; Azure, M.T.; Goddu, S.M.; Howell, R.W.; Rao, D.V. Vitamins as radioprotectors in vivo. II. Protection by vitamin A and soybean oil against radiation damage caused by internal radionuclides. Radiat. Res.,  1994, 139(1), 115-122.
[http://dx.doi.org/10.2307/3578741] [PMID: 8016300] 
[57] 
Srinivasan, V.; Weiss, J.F. Radioprotection by vitamin E: Injectable vitamin E administered alone or with WR-3689 enhances survival of irradiated mice. Int. J. Radiat. Oncol. Biol. Phys.,  1992, 23(4), 841-845.
[http://dx.doi.org/10.1016/0360-3016(92)90657-4] [PMID: 1319980] 
[58] 
Nair, C.K.; Devi, P.U.; Shimanskaya, R.; Kunugita, N.; Murase, H.; Gu, Y.H.; Kagiya, T.V. Water soluble vitamin E (TMG) as a radiopro-tector. Indian J. Exp. Biol.,  2003, 41(12), 1365-1371.
[PMID: 15320488] 
[59] 
Konopacka, M.; Rzeszowska-Wolny, J. Antioxidant vitamins C, E and beta-carotene reduce DNA damage before as well as after gamma-ray irradiation of human lymphocytes in vitro. Mutat. Res.,  2001, 491(1-2), 1-7.
[http://dx.doi.org/10.1016/S1383-5718(00)00133-9] [PMID: 11287291] 
[60] 
Felemovicius, I.; Bonsack, M.E.; Baptista, M.L.; Delaney, J.P. Intestinal radioprotection by vitamin E (alpha-tocopherol). Ann. Surg.,  1995, 222(4), 504-508.
[http://dx.doi.org/10.1097/00000658-199522240-00008] [PMID: 7574930] 
[61] 
Roman, M.; Jitaru, P.; Barbante, C. Selenium biochemistry and its role for human health. Metallomics,  2014, 6(1), 25-54.
[http://dx.doi.org/10.1039/C3MT00185G] [PMID: 24185753] 
[62] 
Tinggi, U. Selenium: Its role as antioxidant in human health. Environ. Health Prev. Med.,  2008, 13(2), 102-108.
[http://dx.doi.org/10.1007/s12199-007-0019-4] [PMID: 19568888] 
[63] 
Reiter, R.J.; Manchester, L.C.; Tan, D.X. Neurotoxins: Free radical mechanisms and melatonin protection. Curr. Neuropharmacol.,  2010, 8(3), 194-210.
[http://dx.doi.org/10.2174/157015910792246236] [PMID: 21358970] 
[64] 
Shirazi, A.; Mihandoost, E.; Mohseni, M.; Ghazi-Khansari, M.; Rabie Mahdavi, S. Radio-protective effects of melatonin against irradia-tion-induced oxidative damage in rat peripheral blood. Phys. Med.,  2013, 29(1), 65-74.
[http://dx.doi.org/10.1016/j.ejmp.2011.11.007] [PMID: 22177584] 
[65] 
Mihandoost, E.; Shirazi, A.; Mahdavi, S.R.; Aliasgharzadeh, A. Can melatonin help us in radiation oncology treatments? BioMed Res. Int.,  2014, 2014, 578137.
[http://dx.doi.org/10.1155/2014/578137] [PMID: 24900972] 
[66] 
Shirazi, A.; Ghobadi, G.; Ghazi-Khansari, M. A radiobiological review on melatonin: A novel radioprotector. J. Radiat. Res. (Tokyo),  2007, 48(4), 263-272.
[http://dx.doi.org/10.1269/jrr.06070] [PMID: 17641465] 
[67] 
Koc, M.; Taysi, S.; Buyukokuroglu, M.E.; Bakan, N. Melatonin protects rat liver against irradiation-induced oxidative injury. J. Radiat. Res. (Tokyo),  2003, 44(3), 211-215.
[http://dx.doi.org/10.1269/jrr.44.211] [PMID: 14646223] 
[68] 
Karslioğlu, I.; Ertekin, M.V.; Taysi, S.; Koçer, I.; Sezen, O.; Gepdiremen, A.; Koç, M.; Bakan, N. Radioprotective effects of melatonin on radiation-induced cataract. J. Radiat. Res. (Tokyo),  2005, 46(2), 277-282.
[http://dx.doi.org/10.1269/jrr.46.277] [PMID: 15988147] 
[69] 
Kamran, M.Z.; Gude, R.P. Preclinical evaluation of the antimetastatic efficacy of Pentoxifylline on A375 human melanoma cell line. Biomed. Pharmacother.,  2012, 66(8), 617-626.
[http://dx.doi.org/10.1016/j.biopha.2012.03.006] [PMID: 23089470] 
[70] 
Kamran, M.Z.; Gude, R.P. Pentoxifylline inhibits melanoma tumor growth and angiogenesis by targeting STAT3 signaling pathway. Biomed. Pharmacother.,  2013, 67(5), 399-405.
[http://dx.doi.org/10.1016/j.biopha.2013.03.020] [PMID: 23639230] 
[71] 
Chiao, T.B.; Lee, A.J. Role of pentoxifylline and vitamin E in attenuation of radiation-induced fibrosis. Ann. Pharmacother.,  2005, 39(3), 516-522.
[http://dx.doi.org/10.1345/aph.1E186] [PMID: 15701781] 
[72] 
Hebbar, S.A.; Mitra, A.K.; George, K.C.; Verma, N.C. Caffeine ameliorates radiation-induced skin reactions in mice but does not influence tumour radiation response. J. Radiol. Prot.,  2002, 22(1), 63-69.
[http://dx.doi.org/10.1088/0952-4746/22/1/306] [PMID: 11929115] 
[73] 
Kandaswami, C.; Middleton, E., Jr Free radical scavenging and antioxidant activity of plant flavonoids. Adv. Exp. Med. Biol.,  1994, 366, 351-376.
[http://dx.doi.org/10.1007/978-1-4615-1833-4_25] [PMID: 7771265] 
[74] 
Benković V.; Orsolić N.; Knezević A.H.; Ramić S.; Dikić D.; Basić I.; Kopjar, N. Evaluation of the radioprotective effects of propolis and flavonoids in gamma-irradiated mice: The alkaline comet assay study. Biol. Pharm. Bull.,  2008, 31(1), 167-172.
[http://dx.doi.org/10.1248/bpb.31.167] [PMID: 18175964] 
[75] 
Hosseinimehr, S.J. Trends in the development of radioprotective agents. Drug Discov. Today,  2007, 12(19-20), 794-805.
[http://dx.doi.org/10.1016/j.drudis.2007.07.017] [PMID: 17933679] 
[76] 
Ahaskar, M.; Sharma, K.V.; Singh, S.; Sisodia, R. Radioprotective effect of fruit extract of grewia asiatica in swiss albino mice against lethal dose of γ irradiation. Asian J. Exp. Sci.,  2007, 21(2)
[77] 
Sharma, K.V.; Sisodia, R. Radioprotective potential of grewia asiatica fruit extract in mice testis. Pharmacologyonline,  2010, 1, 487-495.
[78] 
Sisodia, R.; Ahaskar, M.; Sharma, K.V.; Singh, S. Modulation of radiation-induced biochemical changes in cerebrum of Swiss albino mice by Grewia Asiatica. Acta Neurobiol. Exp. (Warsz.),  2008, 68(1), 32-38.
[PMID: 18389012] 
[79] 
Dhankhar, S.; Ruhil, S.; Balhara, M.; Dhankhar, S.; Chhillar, A.K. Aegle marmelos (Linn.)Correa: A potential source of Phytomedicine. J. Med. Plants Res.,  2011, 5(9), 1497-1507.
[80] 
Jagetia, G.C.; Venkatesh, P.; Baliga, M.S. Evaluation of the radioprotective effect of bael leaf (Aegle marmelos) extract in mice. Int. J. Radiat. Biol.,  2004, 80(4), 281-290.
[http://dx.doi.org/10.1080/09553000410001679776] [PMID: 15204705] 
[81] 
Baliga, M.S.; Bhat, H.P.; Pereira, M.M.; Mathias, N.; Venkatesh, P. Radioprotective effects of Aegle marmelos (L.) Correa (Bael): a concise review. J. Altern. Complement. Med.,  2010, 16(10), 1109-1116.
[http://dx.doi.org/10.1089/acm.2009.0604] [PMID: 20932194] 
[82] 
Jagetia, G.C.; Venkatesh, P.; Baliga, M.S. Fruit extract of Aegle marmelos protects mice against radiation-induced lethality. Integr. Cancer Ther.,  2004, 3(4), 323-332.
[http://dx.doi.org/10.1177/1534735404270641] [PMID: 15523103] 
[83] 
Jagetia, G.C.; Venkatesh, P.; Baliga, M.S. Evaluation of the radioprotective effect of Aegle marmelos (L.) correa in cultured human periph-eral blood lymphocytes exposed to different doses of γ-radiation: a micronucleus study. Mutagenesis,  2003, 18(4), 387-393.
[http://dx.doi.org/10.1093/mutage/geg011] [PMID: 12840113] 
[84] 
Yadav, O.V.; Mulla, R.R.; Patel, N.A.; Shende, S.S.; Yankanchi, S.R. Evaluation of Aegle marmelos L. Fruit extract in reduction of mobile phone induced oxidative stress in mice, Mus musculus. Int. J. Life Sci.,  2018, 6(1), 123-130.
[85] 
Rahman, A.; Imran, H.; Iqbal, L. STaqvi, S.I.; Fatima, N.; Yaqeen, Z. Dry and ripe fruit of Aegle marmelos. L: A potent source of antioxi-dant, lipoxygenase inhibitors and free radical scavenger. Pak. J. Pharm. Sci.,  2016, 29(4), 1127-1131.
[PMID: 27393425] 
[86] 
Dadupanthi, P. Radioprotection of aloe vera against biochemical alterations in swiss albino mice. Int. J. Curr. Pharm. Res.,  2018, 10(3), 55-59.
[http://dx.doi.org/10.22159/ijcpr.2018v10i3.27339] 
[87] 
Nejaim, Y.; I.V., Silva A.; V Vasconcelos, T.; J N L Silva, E.; M de Almeida, S. Evaluation of radioprotective effect of aloe vera and zinc/copper compounds against salivary dysfunction in irradiated rats. J. Oral Sci.,  2014, 56(3), 191-194.
[http://dx.doi.org/10.2334/josnusd.56.191] [PMID: 25231144] 
[88] 
Goyal, P.K.; Gehlot, P. Radioprotective effects of Aloe vera leaf extract on Swiss albino mice against whole-body gamma irradiation. J. Environ. Pathol. Toxicol. Oncol.,  2009, 28(1), 53-61.
[http://dx.doi.org/10.1615/JEnvironPatholToxicolOncol.v28.i1.60] [PMID: 19392655] 
[89] 
Kumar, A.; Kumarchandra, R.; Rai, R.; Sanjeev, G. Anticlastogenic, radiation antagonistic, and anti-inflammatory activities of Persea amer-icana in albino Wistar rat model. Res. Pharm. Sci.,  2017, 12(6), 488-499.
[http://dx.doi.org/10.4103/1735-5362.217429] [PMID: 29204177] 
[90] 
Paul, R.; Kulkarni, P.; Ganesh, N. Avocado fruit (Persea americana Mill) exhibits chemo-protective potentiality against cyclophosphamide induced genotoxicity in human lymphocyte culture. J. Exp. Ther. Oncol.,  2011, 9(3), 221-230.
[PMID: 22070054] 
[91] 
Batcioglu, K.; Yilmaz, Z.; Satilmis, B.; Uyumlu, A.B.; Erkal, H.S.; Yucel, N.; Gunal, S.; Serin, M.; Demirtas, H. Investigation of in vivo radioprotective and in vitro antioxidant and antimicrobial activity of garlic (Allum sativum). Eur. Rev. Med. Pharmacol. Sci.,  2012, 16(3)(Suppl. 3), 47-57.
[PMID: 22957418] 
[92] 
Rao, S.N.; Shetty, S. SuchethaKumari, N.; Madhu, L. N.; Sanjeev, G. Radioprotective properties of Allium sativum (garlic) extract on cul-tured human lymphocytes against electron beam radiation. Int. J. Pharm. Sci. Drug Res.,  2015, 7(2), 151-156.
[93] 
Premanath, R.; Lakshmidevi, N. Studies on anti-oxidant activity of Tinospora cordifolia (Miers.) leaves using in vitro models. J. Am. Sci.,  2010, 6, 736-743.
[94] 
Goel, H.C.; Prasad, J.; Singh, S.; Sagar, R.K.; Agrawala, P.K.; Bala, M.; Sinha, A.K.; Dogra, R. Radioprotective potential of an herbal extract of Tinospora cordifolia. J. Radiat. Res. (Tokyo),  2004, 45(1), 61-68.
[http://dx.doi.org/10.1269/jrr.45.61] [PMID: 15133291] 
[95] 
Patel, A.; Bigoniya, P.; Singh, C.S.; Patel, N.S. Radioprotective and cytoprotective activity of Tinospora cordifolia stem enriched extract containing cordifolioside-A. Indian J. Pharmacol.,  2013, 45(3), 237-243.
[http://dx.doi.org/10.4103/0253-7613.111919] [PMID: 23833365] 
[96] 
Subramanian, M.; Chintalwar, G.J.; Chattopadhyay, S. Radioprotective property of polysaccharide in Tinospora cordifolia. Indian J. Biochem. Biophys.,  2003, 40(1), 22-26.
[PMID: 22900287] 
[97] 
Amruthesh, S.; Pramod, K.P.R.; Venkatesh, B.A.; Ramesh, C. Evaluation of radioprotective effects of Tinospora cordifolia in patients on radiotherapy for squamous cell carcinoma of the head & neck –A pilot study. Int. J. Contem. Denti.,  2010, 1(1), 24-30.
[98] 
Sandeep, D.; Nair, C. K. Protection of DNA and membrane from γ-
radiation induced damage by the extract of Acorus calamus Linn.:
An in vitro study 2010, 29(3), 302-307.
[99] 
Das, B.K.; Swamy, A.V.; Koti, B.C.; Gadad, P.C. Experimental evidence for use of Acorus calamus (asarone) for cancer chemoprevention. Heliyon,  2019, 5(5), e01585.
[http://dx.doi.org/10.1016/j.heliyon.2019.e01585] [PMID: 31193009] 
[100] 
Gantait, S.; Panigrahi, J. In vitro biotechnological advancements in Malabar nut (Adhatoda vasica Nees): Achievements, status and pro-spects. J. Genet. Eng. Biotechnol.,  2018, 16(2), 545-552.
[http://dx.doi.org/10.1016/j.jgeb.2018.03.007] [PMID: 30733772] 
[101] 
Singh, S.K.; Patel, J.R.; Dangi, A.; Bachle, D.; Kataria, R.K. A complete over review on Adhatoda vasica a traditional medicinal plants. Journal of Medicinal Plants Studies,  2017, 5(1), 175-180.
[102] 
Sharma, P.; Jadon, R.S.; Singh, D.; Ganesh, N. Radiation protective potentiality of Adhatoda vasica. Int. J. Phytomed.,  2009, 1, 39-43.
[http://dx.doi.org/10.5138/ijpm.2009.0975.0185.05792] 
[103] 
Ahmad, R.; Raja, V.; Sharma, M. Hepatoprotective activity of ethyl acetate extract of Adhatoda Vasica in swiss albino rats. Int. J. Curr. Res. Rev.,  2013, 5, 16-21.
[104] 
Apooshan, P.G.; Sundar, K. Anti-ulcer activity of Adhatoda vasica leaves against gastric ulcer in rats anti-ulcer activity. J. Glob. Pharma Technol.,  2011, 3(2), 7-13.
[105] 
Kaur, I.; Kumar, A.; Sharma, S. Effect of administering ethanolic extract of Adhatoda vasica on blood count and sod enzyme activity against exposure to γ – radiations. Int. J. Pharm. Sci. Res.,  2013, 4(10), 4016-4026.
[106] 
Chakraborty, S.; Pithawala, M. Radiomimetic drug – “bleomycin-” induced dna damage repair by alstonia scholaris bark extracts – a g2 assay-based evidence. Innovare. J. Life Sci.,  2019, 7(2), 1-5.
[107] 
Gupta, U.; Jahan, S.; Chaudhary, R.; Goyal, P.K. Amelioration of radiation-induced hematological and biochemical alterations by Alstonia scholaris (a medicinal plant) extract. Integr. Cancer Ther.,  2008, 7(3), 155-161.
[http://dx.doi.org/10.1177/1534735408322850] [PMID: 18815147] 
[108] 
Mistry, D.; Pithawala, M. Protective effect of alstonia scholaris linn. r. br. against bleomycin induced chromosomal damage in cultured human lymphocytes, in vitro. Drug Chem. Toxicol.,  2018, 41(2), 162-168.
[http://dx.doi.org/10.1080/01480545.2017.1329316] [PMID: 28587522] 
[109] 
Jagetia, G.C.; Baliga, M.S. Preclinical evaluation of the anticancer activity of hydroalcoholic stem bark extract of alstonia scholaris in ehrlich ascites carcinoma transplanted in the swiss albino mice. J. Altern. Med. Res.,  2016, 2(2), 115.
[110] 
Zhao, L.; Wang, Y.; Shen, H.L.; Shen, X.D.; Nie, Y.; Wang, Y.; Han, T.; Yin, M.; Zhang, Q.Y. Structural characterization and radioprotec-tion of bone marrow hematopoiesis of two novel polysaccharides from the root of Angelica sinensis (Oliv.) Diels. Fitoterapia,  2012, 83(8), 1712-1720.
[http://dx.doi.org/10.1016/j.fitote.2012.09.029] [PMID: 23063893] 
[111] 
Hua, Y.; Yao, W.; Ji, P.; Wei, Y. Integrated metabonomic-proteomic studies on blood enrichment effects of Angelica sinensis on a blood deficiency mice model. Pharm. Biol.,  2017, 55(1), 853-863.
[http://dx.doi.org/10.1080/13880209.2017.1281969] [PMID: 28140733] 
[112] 
Ting, S.; Linjin, Y.; Wenyi, L.; Ping, L.; Kun, J.; Zhang, Z.L. Anti-cancer activity of an ethyl-acetate extract of the fruits of Terminalia bellerica (Gaertn.) Roxb. through an apoptotic signaling pathway in vitro. J. Trad. Chin. Med. Sci.,  2018, 5(4), 370-379.
[http://dx.doi.org/10.1016/j.jtcms.2018.11.006] 
[113] 
Jain, M.; Sisodia, R.; Bhatia, A.I. Studies of methanolic extract of Amaranthus paniculatus L on Mice Liver against; IRPA: Spain, 2004. 
[114] 
Yadav, R.K.; Seth, G.B.; Bhatia, A.L.; Sisodia, R. Modulation of radiation induced biochemical changes in testis of swiss albino mice by Amaranthus paniculatus Linn. Asian J. Exp. Sci.,  2004, 18(1&2), 63-74.
[115] 
Krishna, A.; Kumar, A. Evaluation of radioprotective effects of Rajgira (Amaranthus paniculatus) extract in Swiss albino mice. J. Radiat. Res. (Tokyo),  2005, 46(2), 233-239.
[http://dx.doi.org/10.1269/jrr.46.233] [PMID: 15988142] 
[116] 
Jagetia, G.C.; Venkatesha, V.A. Determination of antineoplastic activity of Rohituka, aphanamixis polystachya (wall) rn parker in hela cells: Correlation with clonogenicity and dna damage. Int. J. Complement. Altern. Med.,  2016, 3(4), 00083.
[http://dx.doi.org/10.15406/ijcam.2016.03.00083] 
[117] 
Guruvayoorappan, C.; Kuttan, G. Protective effect of Biophytum sensitivum (L.) DC on radiation-induced damage in mice. Immunopharmacol. Immunotoxicol.,  2008, 30(4), 815-835.
[http://dx.doi.org/10.1080/08923970802439480] [PMID: 18951225] 
[118] 
Sakthivel, K.M.; Guruvayoorappan, C. Biophytum sensitivum: Ancient medicine, modern targets. J. Adv. Pharm. Technol. Res.,  2012, 3(2), 83-91.
[http://dx.doi.org/10.4103/2231-4040.97279] [PMID: 22837955] 
[119] 
Guruvayoorappan, C.; Kuttan, G. Immunomodulatory and antitumor activity of Biophytum sensitivum extract. Asian Pac. J. Cancer Prev.,  2007, 8(1), 27-32.
[PMID: 17477767] 
[120] 
Manu, K.A.; Leyon, P.V.; Kuttan, G. Studies on the protective effects of Boerhaavia diffusa L. against gamma radiation induced damage in mice. Integr. Cancer Ther.,  2007, 6(4), 381-388.
[http://dx.doi.org/10.1177/1534735407309743] [PMID: 18048886] 
[121] 
Jagetia, G.C.; Shetty, P.C.; Vidyasagar, M.S. Inhibition of radiation-induced DNA damage by jamun, Syzygium cumini, in the cultured sple-nocytes of mice exposed to different doses of γ-radiation. Integr. Cancer Ther.,  2012, 11(2), 141-153.
[http://dx.doi.org/10.1177/1534735411413261] [PMID: 21733986] 
[122] 
Sharma, J.; Sharma, R. Radioprotection of swiss albino mouse by Centella asiatica extract. Phytother. Res.,  2002, 16(8), 785-786.
[http://dx.doi.org/10.1002/ptr.1069] [PMID: 12458490] 
[123] 
Song, J.Y.; Yang, H.O.; Shim, J.Y. Ji-Yeon-Ahn; Han, Y.S.; Jung, I.S.; Yun, Y.S. Radiation protective effect of an extract from Cheli-donium majus. Int. J. Hematol.,  2003, 78(3), 226-232.
[http://dx.doi.org/10.1007/BF02983799] [PMID: 14604281] 
[124] 
Inano, H.; Onoda, M. Radioprotective action of curcumin extracted from Curcuma longa LINN: inhibitory effect on formation of urinary 8-hydroxy-2′-deoxyguanosine, tumorigenesis, but not mortality, induced by gamma-ray irradiation. Int. J. Radiat. Oncol. Biol. Phys.,  2002, 53(3), 735-743.
[http://dx.doi.org/10.1016/S0360-3016(02)02794-3] [PMID: 12062620] 
[125] 
Mansourian, A.; Amanlou, M.; Shirazian, S.; Jahromi, Z.M.; Amirian, A. “The effect of Curcuma Longa” topical gel on radiation;induced oral mucositis in patients with head and neck cancer. Int. J. Radia. Res.,  2015, 13(3), 269-274.
[126] 
Nada, A.S.; Hawas, A.M. Amin, Nel-D.; Elnashar, M.M.; Abd Elmageed, Z.Y. Radioprotective effect of Curcuma longa extract on γ-irradiation-induced oxidative stress in rats. Can. J. Physiol. Pharmacol.,  2012, 90(4), 415-423.
[http://dx.doi.org/10.1139/y2012-005] [PMID: 22432737] 
[127] 
Srinivasan, M.; Rajendra Prasad, N.; Menon, V.P. Protective effect of curcumin on gamma-radiation induced DNA damage and lipid pe-roxidation in cultured human lymphocytes. Mutat. Res.,  2006, 611(1-2), 96-103.
[http://dx.doi.org/10.1016/j.mrgentox.2006.07.002] [PMID: 16973408] 
[128] 
Goel, A.; Aggarwal, B.B. Curcumin, the golden spice from Indian saffron, is a chemosensitizer and radiosensitizer for tumors and chemo-protector and radioprotector for normal organs. Nutr. Cancer,  2010, 62(7), 919-930.
[http://dx.doi.org/10.1080/01635581.2010.509835] [PMID: 20924967] 
[129] 
Qian, Y.; Ma, J.; Guo, X.; Sun, J.; Yu, Y.; Cao, B.; Zhang, L.; Ding, X.; Huang, J.; Shao, J.F. Curcumin enhances the radiosensitivity of U87 cells by inducing DUSP-2 up-regulation. Cell. Physiol. Biochem.,  2015, 35(4), 1381-1393.
[http://dx.doi.org/10.1159/000373959] [PMID: 25792385] 
[130] 
Singh, I.; Sharma, A.; Jindal, A.; Soyal, D.; Goyal, P.K. Protective effect of Emblica officinalis fruit extract against gamma irradiation in mice. Pharmacologyonline,  2006, 2, 128-150.
[131] 
Jagetia, G.C.; Baliga, M.S.; Malagi, K.J.; Sethukumar Kamath, M. The evaluation of the radioprotective effect of Triphala (an ayurvedic rejuvenating drug) in the mice exposed to γ-radiation. Phytomedicine,  2002, 9(2), 99-108.
[http://dx.doi.org/10.1078/0944-7113-00095] [PMID: 11995956] 
[132] 
Singh, I. Modification of serum phosphatases activity against whole-body irradiation in mice by embilica officinalis fruit extract. Remark-ing An Analisation,  2019, 3(12), E388-E393.
[133] 
Imosemi, I.O.; Owolabi, I.S.; Owoeye, O.; Malomo, A.O. Protective effect of Carica papaya fruit extract against gamma radiation-induced oxidative damage in postnatal developing rat cerebellum. Afr. J. Biomed. Res.,  2018, 21, 73-80.
[134] 
Hosseinimehr, S.J.; Azadbakht, M.; Mousavi, S.M.; Mahmoudzadeh, A.; Akhlaghpoor, S. Radioprotective effects of hawthorn fruit extract against gamma irradiation in mouse bone marrow cells. J. Radiat. Res. (Tokyo),  2007, 48(1), 63-68.
[http://dx.doi.org/10.1269/jrr.06032] [PMID: 17185880] 
[135] 
Abou-Zeid, S.M.; El-Bialy, B.E.; El-Borai, N.B.; AbuBakr, H.O.; Elhadary, A.M.A. Radioprotective effect of Date syrup on radiation- induced damage in Rats. Sci. Rep.,  2018, 8(1), 7423.
[http://dx.doi.org/10.1038/s41598-018-25586-3] [PMID: 29743497] 
[136] 
Dauer, A.; Metzner, P.; Schimmer, O. Proanthocyanidins from the bark of Hamamelis virginiana exhibit antimutagenic properties against nitroaromatic compounds. Planta Med.,  1998, 64(4), 324-327.
[http://dx.doi.org/10.1055/s-2006-957443] [PMID: 9619113] 
[137] 
Birosová, L.; Mikulásová, M.; Vaverková, S. Antimutagenic effect of phenolic acids. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub.,  2005, 149(2), 489-491.
[http://dx.doi.org/10.5507/bp.2005.087] [PMID: 16601817] 
[138] 
Düsman, E.; Berti, A.P.; Mariucci, R.G.; Lopes, N.B.; Tonin, L.T.; Vicentini, V.E.; Vicentini, V.E.P. Radioprotective effect of the Barbados Cherry (Malpighia glabra L.) against radiopharmaceutical iodine-131 in Wistar rats in vivo. BMC Complement. Altern. Med.,  2014, 14, 41.
[http://dx.doi.org/10.1186/1472-6882-14-41] [PMID: 24479389] 
[139] 
Lampronti, I.; Martello, D.; Bianchi, N.; Borgatti, M.; Lambertini, E.; Piva, R.; Jabbar, S.; Choudhuri, M.S.; Khan, M.T.; Gambari, R. In vitro antiproliferative effects on human tumor cell lines of extracts from the bangladeshi medicinal plant aegle marmelos correa. Phytomedicine,  2003, 10(4), 300-308.
[http://dx.doi.org/10.1078/094471103322004794] [PMID: 12809360] 
[140] 
Lambertini, E.; Piva, R.; Khan, M.T.; Lampronti, I.; Bianchi, N.; Borgatti, M.; Gambari, R. Effects of extracts from Bangladeshi medicinal plants on in vitro proliferation of human breast cancer cell lines and expression of estrogen receptor α gene. Int. J. Oncol.,  2004, 24(2), 419-423.
[http://dx.doi.org/10.3892/ijo.24.2.419] [PMID: 14719119] 
[141] 
Jagetia, G.C.; Venkatesh, P.; Baliga, M.S. Aegle marmelos (L.) Correa inhibits the proliferation of transplanted Ehrlich ascites carcinoma in mice. Biol. Pharm. Bull.,  2005, 28(1), 58-64.
[http://dx.doi.org/10.1248/bpb.28.58] [PMID: 15635164] 
[142] 
Son, E.W.; Mo, S.J.; Rhee, D.K.; Pyo, S. Inhibition of ICAM-1 expression by garlic component, allicin, in gamma-irradiated human vascu-lar endothelial cells via downregulation of the JNK signaling pathway. Int. Immunopharmacol.,  2006, 6(12), 1788-1795.
[http://dx.doi.org/10.1016/j.intimp.2006.07.021] [PMID: 17052669] 
[143] 
Jaiswal, S.K.; Bordia, A. Radio-protective effect of garlic Allium sativum Linn. in albino rats. Indian J. Med. Sci.,  1996, 50(7), 231-233.
[PMID: 8979540] 
[144] 
Thomson, M.; Ali, M. Garlic [Allium sativum]: A review of its potential use as an anti-cancer agent. Curr. Cancer Drug Targets,  2003, 3(1), 67-81.
[http://dx.doi.org/10.2174/1568009033333736] [PMID: 12570662] 
[145] 
Rajagopal, S.; Kumar, R.A.; Deevi, D.S.; Satyanarayana, C.; Rajagopalan, R. Andrographolide, a potential cancer therapeutic agent isolated from Andrographis paniculata. J. Exp. Ther. Oncol.,  2003, 3(3), 147-158.
[http://dx.doi.org/10.1046/j.1359-4117.2003.01090.x] [PMID: 14641821] 
[146] 
Kumar, R.A.; Sridevi, K.; Kumar, N.V.; Nanduri, S.; Rajagopal, S. Anticancer and immunostimulatory compounds from Andrographis paniculata. J. Ethnopharmacol.,  2004, 92(2-3), 291-295.
[http://dx.doi.org/10.1016/j.jep.2004.03.004] [PMID: 15138014] 
[147] 
Tripathi, R.; Kamat, J.P. Free radical induced damages to rat liver subcellular organelles: Inhibition by Andrographis paniculata extract. Indian J. Exp. Biol.,  2007, 45(11), 959-967.
[PMID: 18072540] 
[148] 
Varma, A.; Padh, H.; Shrivastava, N. Andrographolide: A new plant-derived antineoplastic entity on horizon. Evid. Based Complement. Alternat. Med.,  2011, 2011, 815390.
[http://dx.doi.org/10.1093/ecam/nep135] [PMID: 19752167] 
[149] 
Han, G.; Zhou, Y.F.; Zhang, M.S.; Cao, Z.; Xie, C.H.; Zhou, F.X.; Peng, M.; Zhang, W.J. Angelica sinensis down-regulates hydroxyproline and Tgfb1 and provides protection in mice with radiation-induced pulmonary fibrosis. Radiat. Res.,  2006, 165(5), 546-552.
[http://dx.doi.org/10.1667/RR3543.1] [PMID: 16669709] 
[150] 
Jahan, S.; Goyal, P.K. Protective effect of Alstonia scholaris against radiation-induced clastogenic and biochemical alterations in mice. J. Environ. Pathol. Toxicol. Oncol.,  2010, 29(2), 101-111.
[http://dx.doi.org/10.1615/JEnvironPatholToxicolOncol.v29.i2.40] [PMID: 20932245] 
[151] 
Babu, T.D.; Kuttan, G.; Padikkala, J. Cytotoxic and anti-tumour properties of certain taxa of Umbelliferae with special reference to Centella asiatica (L.). Urban. J. Ethnopharmacol.,  1995, 48(1), 53-57.
[http://dx.doi.org/10.1016/0378-8741(95)01284-K] [PMID: 8569247] 
[152] 
Yoshida, M.; Fuchigami, M.; Nagao, T.; Okabe, H.; Matsunaga, K.; Takata, J.; Karube, Y.; Tsuchihashi, R.; Kinjo, J.; Mihashi, K.; Fujioka, T. Antiproliferative constituents from Umbelliferae plants VII. Active triterpenes and rosmarinic acid from Centella asiatica. Biol. Pharm. Bull.,  2005, 28(1), 173-175.
[http://dx.doi.org/10.1248/bpb.28.173] [PMID: 15635187] 
[153] 
Cheng, A.L.; Hsu, C.H.; Lin, J.K.; Hsu, M.M.; Ho, Y.F.; Shen, T.S.; Ko, J.Y.; Lin, J.T.; Lin, B.R.; Ming-Shiang, W.; Yu, H.S.; Jee, S.H.; Chen, G.S.; Chen, T.M.; Chen, C.A.; Lai, M.K.; Pu, Y.S.; Pan, M.H.; Wang, Y.J.; Tsai, C.C.; Hsieh, C.Y. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res.,  2001, 21(4B), 2895-2900.
[PMID: 11712783] 
[154] 
Kuttan, R.; Bhanumathy, P.; Nirmala, K.; George, M.C. Potential anticancer activity of turmeric (Curcuma longa). Cancer Lett.,  1985, 29(2), 197-202.
[http://dx.doi.org/10.1016/0304-3835(85)90159-4] [PMID: 4075289] 
[155] 
Zhang, J.; Qi, H.; Wu, C. Research of anti-proliferation of curcumin on A549 human lung cancer cells and its mechanism. Zhong Yao Cai,  2004, 27(12), 923-927.
[PMID: 15807244] 
[156] 
Aggarwal, B.B.; Kumar, A.; Aggarwal, M.S.; Shishodia, S. Curcumin derived from turmeric (Curcuma longa): A spice for all seasons. Phy-topharmaceuticals in Cancer Chemoprevention,  2005, 23, 351-387.
[157] 
Bharti, A.C.; Donato, N.; Singh, S.; Aggarwal, B.B. Curcumin down-regulates the constitutive activation of nuclear factor ${\kappa} $ B and $ I {\kappa} B {\alpha} $ kinase in human multiple myeloma cells leading to suppression of proliferation and induction of apoptosis. Blood,  2003, 101(3), 1052-1062.
[http://dx.doi.org/10.1182/blood-2002-05-1320] [PMID: 12393461] 
[158] 
Dorai, T.; Aggarwal, B.B. Role of chemopreventive agents in cancer therapy. Cancer Lett.,  2004, 215(2), 129-140.
[http://dx.doi.org/10.1016/j.canlet.2004.07.013] [PMID: 15488631] 
[159] 
Jose, J.K.; Kuttan, G.; Kuttan, R. Antitumour activity of Emblica officinalis. J. Ethnopharmacol.,  2001, 75(2-3), 65-69.
[http://dx.doi.org/10.1016/S0378-8741(00)00378-0] [PMID: 11297836] 
[160] 
Singh, I.; Sharma, A.; Nunia, V.; Goyal, P.K. Radioprotection of Swiss albino mice by Emblica officinalis. Phytother. Res.,  2005, 19(5), 444-446.
[http://dx.doi.org/10.1002/ptr.1600] [PMID: 16106381] 
[161] 
Agrawala, P.K.; Goel, H.C. Protective effect of RH-3 with special reference to radiation induced micronuclei in mouse bone marrow. Indi-an. J. Exp. Biol.,  2002, 40(5), 525-530.
[PMID: 12622196] 
[162] 
Goel, H.C.; Kumar, I.P.; Samanta, N.; Rana, S.V. Induction of DNA-protein cross-links by Hippophae rhamnoides: Implications in radio-protection and cytotoxicity. Mol. Cell. Biochem.,  2003, 245(1-2), 57-67.
[http://dx.doi.org/10.1023/A:1022809625826] [PMID: 12708745] 
[163] 
Goel, H.C.; Gupta, D.; Gupta, S.; Garg, A.P.; Bala, M. Protection of mitochondrial system by Hippophae rhamnoides L. against radiation-induced oxidative damage in mice. J. Pharm. Pharmacol.,  2005, 57(1), 135-143.
[http://dx.doi.org/10.1211/0022357055218] [PMID: 15639001] 
[164] 
Patel, C.A.; Divakar, K.; Santani, D.; Solanki, H.K.; Thakkar, J.H. Remedial prospective of Hippophaë rhamnoides Linn.(sea buckthorn). ISRN Pharmacol.,  2012, 2012.
[165] 
Smyshliaeva, A.V.; Nguyen, L.H.; Kudriashov, I. The modification of a radiation lesion in animals with an aqueous extract of Hypericum perforatum L. In Nauchnye doklady vysshei shkoly. Biologicheskie nauki,  1992, 4, 9-13.
[166] 
Jagetia, G.C.; Baliga, M.S. Influence of the leaf extract of Mentha arvensis Linn. (mint) on the survival of mice exposed to different doses of gamma radiation. Strahlenther. Onkol.,  2002, 178(2), 91-98.
[http://dx.doi.org/10.1007/s00066-002-0841-y] [PMID: 11942043] 
[167] 
Samarth, R.M.; Kumar, A. Mentha piperita (Linn.) leaf extract provides protection against radiation induced chromosomal damage in bone marrow of mice. Indian J. Exp. Biol.,  2003, 41(3), 229-237.
[PMID: 15267153] 
[168] 
Liu, C.P.; Tsai, W.J.; Lin, Y.L.; Liao, J.F.; Chen, C.F.; Kuo, Y.C. The extracts from Nelumbo Nucifera suppress cell cycle progression, cytokine genes expression, and cell proliferation in human peripheral blood mononuclear cells. Life Sci.,  2004, 75(6), 699-716.
[http://dx.doi.org/10.1016/j.lfs.2004.01.019] [PMID: 15172179] 
[169] 
Duan, Y.; Zhang, H.; Xie, B.; Yan, Y.; Li, J.; Xu, F.; Qin, Y. Whole body radioprotective activity of an acetone-water extract from the seedpod of Nelumbo nucifera Gaertn. seedpod. Food Chem. Toxicol.,  2010, 48(12), 3374-3384.
[http://dx.doi.org/10.1016/j.fct.2010.09.008] [PMID: 20837084] 
[170] 
Ranga, R.S.; Sowmyalakshmi, S.; Burikhanov, R.; Akbarsha, M.A.; Chendil, D. A herbal medicine for the treatment of lung cancer. Mol. Cell. Biochem.,  2005, 280(1-2), 125-133.
[http://dx.doi.org/10.1007/s11010-005-8518-3] [PMID: 16311913] 
[171] 
Ganasoundari, A.; Devi, P.U.; Rao, B.S. Enhancement of bone marrow radioprotection and reduction of WR-2721 toxicity by Ocimum sanctum. Mutat. Res.,  1998, 397(2), 303-312.
[http://dx.doi.org/10.1016/S0027-5107(97)00230-3] [PMID: 9541656] 
[172] 
Pattanayak, P.; Behera, P.; Das, D.; Panda, S.K. Ocimum sanctum Linn. A reservoir plant for therapeutic applications: An overview. Pharmacogn. Rev.,  2010, 4(7), 95-105.
[http://dx.doi.org/10.4103/0973-7847.65323] [PMID: 22228948] 
[173] 
Vrinda, B.; Uma Devi, P. Radiation protection of human lymphocyte chromosomes in vitro by orientin and vicenin. Mutat. Res.,  2001, 498(1-2), 39-46.
[http://dx.doi.org/10.1016/S1383-5718(01)00263-7] [PMID: 11673069] 
[174] 
Goel, H.C.; Prasad, J.; Sharma, A.; Singh, B. Antitumour and radioprotective action of Podophyllum hexandrum. Indian J. Exp. Biol.,  1998, 36(6), 583-587.
[PMID: 9731473] 
[175] 
Giri, A.; Lakshmi Narasu, M. Production of podophyllotoxin from Podophyllum hexandrum: A potential natural product for clinically useful anticancer drugs. Cytotechnology,  2000, 34(1-2), 17-26.
[http://dx.doi.org/10.1023/A:1008138230896] [PMID: 19003377] 
[176] 
Goel, H.C.; Sajikumar, S.; Sharma, A. Effects of Podophyllum hexandrum on radiation induced delay of postnatal appearance of reflexes and physiological markers in rats irradiated in utero. Phytomedicine,  2002, 9(5), 447-454.
[http://dx.doi.org/10.1078/09447110260571715] [PMID: 12222667] 
[177] 
Chawla, R.; Arora, R.; Sagar, R.K.; Singh, S.; Puri, S.C.; Kumar, R.; Singh, S.; Sharmaa, A.K.; Prasada, J.; Khan, H.A.; Sharma, R.K.; Dhar, K.L.; Spiteller, M.; Qazi, G.N. 3-O-β-D-Galactopyranoside of quercetin as an active principle from high altitude Podophyllum hexandrum and evaluation of its radioprotective properties. Z. Naturforsch. C J. Biosci.,  2005, 60(9-10), 728-738.
[http://dx.doi.org/10.1515/znc-2005-9-1012] [PMID: 16320616] 
[178] 
Prem Kumar, I.; Rana, S.V.; Samanta, N.; Goel, H.C. Enhancement of radiation-induced apoptosis by Podophyllum hexandrum. J. Pharm. Pharmacol.,  2003, 55(9), 1267-1273.
[http://dx.doi.org/10.1211/0022357021738] [PMID: 14604470] 
[179] 
Eder-Czembirek, C.; Erovic, B.M.; Czembirek, C.; Brunner, M.; Selzer, E.; Pötter, R.; Thurnher, D. Betulinic acid a radiosensitizer in head and neck squamous cell carcinoma cell lines. Strahlenther. Onkol.,  2010, 186(3), 143-148.
[http://dx.doi.org/10.1007/s00066-010-2069-6] [PMID: 20339825] 
[180] 
Klautke, G.; Küchenmeister, U.; Foitzik, T.; Ludwig, K.; Prall, F.; Klar, E.; Fietkau, R. Concurrent chemoradiation with capecitabine and weekly irinotecan as preoperative treatment for rectal cancer: results from a phase I/II study. Br. J. Cancer,  2006, 94(7), 976-981.
[http://dx.doi.org/10.1038/sj.bjc.6603053] [PMID: 16552435] 
[181] 
Sato, T.; Kokuba, Y.; Koizumi, W.; Hayakawa, K.; Okayasu, I.; Watanabe, M. Phase I trial of neoadjuvant preoperative chemotherapy with S-1 and irinotecan plus radiation in patients with locally advanced rectal cancer. Int. J. Radiat. Oncol. Biol. Phys.,  2007, 69(5), 1442-1447.
[http://dx.doi.org/10.1016/j.ijrobp.2007.05.081] [PMID: 17855009] 
[182] 
Shin, S.J.; Kim, N.K.; Keum, K.C.; Kim, H.G. Im, J.S.; Choi, H.J.; Baik, S.H.; Choen, J.H.; Jeung, H.C.; Rha, S.Y.; Roh, J.K.; Chung, H.C.; Ahn, J.B. Phase II study of preoperative chemoradiotherapy (CRT) with irinotecan plus S-1 in locally advanced rectal cancer. Radiother. Oncol.,  2010, 95(3), 303-307.
[http://dx.doi.org/10.1016/j.radonc.2010.02.003] [PMID: 20211505] 
[183] 
Langer, C.J.; Somer, R.; Litwin, S.; Feigenberg, S.; Movsas, B.; Maiale, C.; Sherman, E.; Millenson, M.; Nicoloau, N.; Huang, C.; Treat, J. Phase I study of radical thoracic radiation, weekly irinotecan, and cisplatin in locally advanced non-small cell lung carcinoma. J. Thorac. Oncol.,  2007, 2(3), 203-209.
[http://dx.doi.org/10.1097/JTO.0b013e318031cd3c] [PMID: 17410043] 
[184] 
Hasselbalch, B.; Lassen, U.; Hansen, S.; Holmberg, M.; Sørensen, M.; Kosteljanetz, M.; Broholm, H.; Stockhausen, M.T.; Poulsen, H.S. Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: A phase II trial. Neuro-oncol.,  2010, 12(5), 508-516.
[PMID: 20406901] 
[185] 
Sheehan, J.; Ionescu, A.; Pouratian, N.; Hamilton, D.K.; Schlesinger, D.; Oskouian, R.J., Jr; Sansur, C. Use of trans sodium crocetinate for sensitizing glioblastoma multiforme to radiation: Laboratory investigation. J. Neurosurg.,  2008, 108(5), 972-978.
[http://dx.doi.org/10.3171/JNS/2008/108/5/0972] [PMID: 18447715] 
[186] 
Gutheil, W.G.; Reed, G.; Ray, A.; Anant, S.; Dhar, A. Crocetin: An agent derived from saffron for prevention and therapy for cancer. Curr. Pharm. Biotechnol.,  2012, 13(1), 173-179.
[http://dx.doi.org/10.2174/138920112798868566] [PMID: 21466430] 
[187] 
Kumar, B.; Joshi, J.; Kumar, A.; Pandey, B.N.; Hazra, B.; Mishra, K.P. Radiosensitization by diospyrin diethylether in MCF-7 breast carci-noma cell line. Mol. Cell. Biochem.,  2007, 304(1-2), 287-296.
[http://dx.doi.org/10.1007/s11010-007-9511-9] [PMID: 17534696] 
[188] 
Kumar, B.; Kumar, A.; Pandey, B.N.; Hazra, B.; Mishra, K.P. Increased cytotoxicity by the combination of radiation and diospyrin diethy-lether in fibrosarcoma in culture and in tumor. Int. J. Radiat. Biol.,  2008, 84(5), 429-440.
[http://dx.doi.org/10.1080/09553000802030736] [PMID: 18464072] 
[189] 
Bae, J.Y.; Choi, J.S.; Kang, S.W.; Lee, Y.J.; Park, J.; Kang, Y.H. Dietary compound ellagic acid alleviates skin wrinkle and inflammation induced by UV-B irradiation. Exp. Dermatol.,  2010, 19(8), e182-e190.
[http://dx.doi.org/10.1111/j.1600-0625.2009.01044.x] [PMID: 20113347] 
[190] 
Bhosle, S.M.; Ahire, V.R.; Henry, M.S.; Thakur, V.S.; Huilgol, N.G.; Mishra, K.P. Augmentation of radiation-induced apoptosis by ellagic acid. Cancer Invest.,  2010, 28(3), 323-330.
[http://dx.doi.org/10.3109/07357900902849616] [PMID: 19863348] 
[191] 
Ozgur, E.; Güler, G.; Seyhan, N. Mobile phone radiation-induced free radical damage in the liver is inhibited by the antioxidants N-acetyl cysteine and epigallocatechin-gallate. Int. J. Radiat. Biol.,  2010, 86(11), 935-945.
[http://dx.doi.org/10.3109/09553002.2010.496029] [PMID: 20807176] 
[192] 
Newcomb, E.W.; Lymberis, S.C.; Lukyanov, Y.; Shao, Y.; Schnee, T.; Devitt, M.; Rosenstein, B.S.; Zagzag, D.; Formenti, S.C. Radiation sensitivity of GL261 murine glioma model and enhanced radiation response by flavopiridol. Cell Cycle,  2006, 5(1), 93-99.
[http://dx.doi.org/10.4161/cc.5.1.2271] [PMID: 16319534] 
[193] 
Raju, U.; Ariga, H.; Koto, M.; Lu, X.; Pickett, J.; Valdecanas, D.; Mason, K.A.; Milas, L. Improvement of esophageal adenocarcinoma cell and xenograft responses to radiation by targeting cyclin-dependent kinases. Radiother. Oncol.,  2006, 80(2), 185-191.
[http://dx.doi.org/10.1016/j.radonc.2006.07.027] [PMID: 16905211] 
[194] 
Raffoul, J.J.; Banerjee, S.; Che, M.; Knoll, Z.E.; Doerge, D.R.; Abrams, J.; Kucuk, O.; Sarkar, F.H.; Hillman, G.G. Soy isoflavones enhance radiotherapy in a metastatic prostate cancer model. Int. J. Cancer,  2007, 120(11), 2491-2498.
[http://dx.doi.org/10.1002/ijc.22548] [PMID: 17304503] 
[195] 
Kimura, Y.; Sumiyoshi, M. Olive leaf extract and its main component oleuropein prevent chronic ultraviolet B radiation-induced skin damage and carcinogenesis in hairless mice. J. Nutr.,  2009, 139(11), 2079-2086.
[http://dx.doi.org/10.3945/jn.109.104992] [PMID: 19776181] 
[196] 
Brand, M.; Sommer, M.; Ellmann, S.; Wuest, W.; May, M.S.; Eller, A.; Vogt, S.; Lell, M.M.; Kuefner, M.A.; Uder, M. Influence of differ-ent antioxidants on X-ray induced DNA double-strand breaks (DSBs) using γ-H2AX immunofluorescence microscopy in a preliminary study. PLoS One,  2015, 10(5), e0127142.
[http://dx.doi.org/10.1371/journal.pone.0127142] [PMID: 25996998] 
[197] 
Kuefner, M.A.; Brand, M.; Ehrlich, J.; Braga, L.; Uder, M.; Semelka, R.C. Effect of antioxidants on X-ray-induced γ-H2AX foci in human blood lymphocytes: preliminary observations. Radiology,  2012, 264(1), 59-67.
[http://dx.doi.org/10.1148/radiol.12111730] [PMID: 22509049] 
[198] 
Xiao, L.; Tsutsui, T.; Miwa, N. The lipophilic vitamin C derivative, 6-o-palmitoylascorbate, protects human lymphocytes, preferentially over ascorbate, against X-ray-induced DNA damage, lipid peroxidation, and protein carbonylation. Mol. Cell. Biochem.,  2014, 394(1-2), 247-259.
[http://dx.doi.org/10.1007/s11010-014-2101-8] [PMID: 24898782] 
[199] 
Alcaraz, M.; Armero, D.; Martínez-Beneyto, Y.; Castillo, J.; Benavente-García, O.; Fernandez, H.; Alcaraz-Saura, M.; Canteras, M. Chemi-cal genoprotection: reducing biological damage to as low as reasonably achievable levels. Dentomaxillofac. Radiol.,  2011, 40(5), 310-314.
[http://dx.doi.org/10.1259/dmfr/95408354] [PMID: 21697157] 
[200] 
Materska, M.; Konopacka, M. Rogoliński, J.; Ślosarek, K. Antioxidant activity and protective effects against oxidative damage of human cells induced by X-radiation of phenolic glycosides isolated from pepper fruits Capsicum annuum L. Food Chem.,  2015, 168, 546-553.
[http://dx.doi.org/10.1016/j.foodchem.2014.07.023] [PMID: 25172746] 
[201] 
Katalinic, V.; Milos, M.; Kulisic, T.; Jukic, M. Screening of 70 medicinal plant extracts for antioxidant capacity and total phenols. Food Chem.,  2006, 94(4), 550-557.
[http://dx.doi.org/10.1016/j.foodchem.2004.12.004] 
[202] 
Smith, T.A.; Kirkpatrick, D.R.; Smith, S.; Smith, T.K.; Pearson, T.; Kailasam, A.; Herrmann, K.Z.; Schubert, J.; Agrawal, D.K. Radiopro-tective agents to prevent cellular damage due to ionizing radiation. J. Transl. Med.,  2017, 15(1), 232.
[http://dx.doi.org/10.1186/s12967-017-1338-x] [PMID: 29121966] 
[203] 
Dowlath, M.J.H.; Karuppannan, S.K.; Sinha, P.; Dowlath, N.S.; Arunachalam, K.D.; Ravindran, B.; Chang, S.W.; Nguyen-Tri, P.; Nguyen, D.D. Effects of radiation and role of plants in radioprotection: A critical review. Sci. Total Environ.,  2021, 779, 146431.
[http://dx.doi.org/10.1016/j.scitotenv.2021.146431] [PMID: 34030282] 
Cite As
Current Pharmaceutical Biotechnology

Review on Natural Bioactive Products as Radioprotective Therapeutics: Present and Past Perspective

Abstract

Graphical Abstract
