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REVIEW ARTICLE
Year : 2022 | Volume
: 14
| Issue : 2 | Page : 57-71
Natural radioprotectors on current and future perspectives: A mini-review
Pooja Shivappa1, Grisilda Vidya Bernhardt2
1 Department of Basic Sciences, Central Research Laboratory, RAK Medical and Health Sciences University, Ras Al Khaimah, UAE
2 Department of Biochemistry, Central Research Laboratory, RAK Medical and Health Sciences University, Ras Al Khaimah, UAE
Correspondence Address:
Dr. Pooja Shivappa
Department of Basic Sciences, Central Research Laboratory, RAK Medical and Health Sciences University, Ras Al Khaimah
UAE
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/jpbs.jpbs_502_21
Abstract
Radiation therapy is used as the primary treatment for cancer. Eighty percent of cancer patients require radiation therapy during treatment or for medical purposes. During treatment, radiation causes various biological defects in the cells. The prevalence of cytotoxicity limits the dose used for effective treatment. This method is designed to strike a balance between removing cancer cells and protecting normal tissues. Unfortunately, effective radiation is unavailable once acute toxicity occurs during clinical radiation therapy. Therefore, a lot of research interest is needed in the discovery of radioprotective drugs to accelerate treatment to reduce this toxicity (i.e., normal tissue toxicity to cancer cell death). Radiation protectors may be chemicals or drugs that minimize the damage caused due to radiation therapy in living organisms. The determination of effective and nontoxic radiation protection is an essential goal for radiation oncologists and basic radiobiologists. However, despite the advantages, many radioprotectors were found to have disadvantages which include cost, less duration, toxicity, and effect on the central nervous system. Therefore in recent years, the focus has been diverted to finding out optimal natural products to act as radioprotectors. Natural radiation protectors are plant compounds that protect normal (noncancerous) cells from damage from radiation therapy. Natural herbal products are nontoxic with proven therapeutic benefits and have long been used to treat various diseases. In conclusion, we find that there are various radiation protectors with different purposes and mechanisms of action.
Keywords: DNA damage, radiation, radioprotectors
Introduction 
Radiation therapy is one of the most effective treatments for cancer patients. Approximately 60% of all cancer patients get ionizing radiation (IR) as part of their treatment procedure.[1] IR is a powerful tool to kill cancer cells, but it is also toxic to normal cells and causes cell damage and various side effects. IR directly or indirectly affects biological molecules. The direct effect of IR is affected by direct contact with different parts of DNA, and indirect effects using reactive oxygen species (ROS) originating from surrounding DNA molecules.[2] Since biological systems contain 75%–90% water, the indirect effect is due to the reaction of water to radiolysis products (OH: hydroxyl radicals, solvent electrons, and hydrogen atoms) with DNA. Hydroxyl groups are highly reactive, have a strong oxidizing effect, and can react differently with all cellular components. DNA, lipids, and proteins are the main targets for hydroxyl radical attack. In response to IR-induced DNA damage, ROS formation, and cell death, the release of damage-related molecules and cytokines or chemokines activates the immune system and causes inflammation. This immune activation results in an acute inflammatory phase characterized by an enhanced anti-inflammatory response. The signaling of inflammation and repair after IR leads to a chronic phase of IR injury, in parallel with mitotic cell death and subsequent release of cytokines and growth factors.[3] It has been observed that multiple diseases are found to be associated with IR response, including diseases caused by acute stage lesions (inflammation of various organs) or chronic stage lesions (blood vessel damage, fibrosis, secondary malignancy, atrophy, and infertility).
Attention has to be provided during IR to protect the healthy cells during the procedure. To this end, technical improvements in the IR delivery procedure, the accuracy of treatment, and pharmacological agents used for the treatment regime are the subject of recent research. The National Cancer Institute's IR Research Program proposed pharmacological classification of the following drugs with IR-protective properties based on the timing of administration: (a) protection, (b) palliative, and (c) therapeutic.[4]
Ideal radioprotective compounds should shield the healthy cells of the body from the harmful effects of the IR but should not prevent the effectiveness of the IR on the tumor cells. Radioprotectors are used as a strategy to avoid exposure to chemicals according to the proposed classification schedule. It is used to prevent acute or chronic effects before radiation therapy or infrared radiation. IR therapy is used during and after treatment to reduce side effects or chronic effects and is administered after the onset of symptoms.[5] Many compounds have been studied as radiation protectors, modifiers, and therapeutics and are currently in the US Food and Drug Administration (FDA) or FDA-Examined New Drug (IND) for approval.[6]
Study Methodology The current article is a mini-review of the existing literature on radioprotectors. A search of the PubMed and Google Scholar was undertaken using the search terms “Radio protectors” “review” in various permutations and combinations. We also searched for referenced papers to identify further studies. A total of 360 review papers on radio protectors out of which 317 papers extending back to the year 2005 using MeSH terms. Out of these 66 papers, were included. Careful literature searches were conducted by going through Google Scholar on the basis of radioprotection 40. papers selected based on protecting humans and animals from the effects of IR. The work outlined here suggests that there are many potential radiation protectors with different purposes and mechanisms. [Figure 1]
Figure 1: Possible mechanism of natural radioprotectors against ionizing radiation-induced damage Radioprotectors Radioprotective agents may be chemicals or drugs that reduce the harm caused when IR therapy is administered to living organisms. Determination of an effective and nontoxic radiation protector is an essential goal for radiation oncologists and basic radiobiologists. The most radioprotective substances to date are amino thiols and their derivatives include aminoethyl isothiouronium bromide hydrobromide (AET), sistemin, and amipocene (WR-2721). Some of these compounds have been used successfully to prevent radiotherapy complications in cancer patients and are believed to protect against radiation risks in clinical use and incidental radiation exposure scenarios.[5] Despite current clinical use, amifostin has not been approved for use in clinical nuclear/radiation conditions. Side effects of amifostin include cost, limited use, and narrow duration, toxicity, effect on the central nervous system.[7] Sulfasalazine (SAZ) is another compound that was reported to protect mice at 120 mg/kg without toxicity. At this dose, SAZ protected the plasmid DNA (pGEM-7Zf) from dissolution from the Fenton reaction, suggesting free radical scavenging as one of the possible mechanisms of radioactivity, but some levels of toxicity have also been observed. The practical applicability of most synthetic compounds was still limited due to their high toxicity. Ideal protective agents provide a high degree of protection against normal tissues, little or no protection against tumor cells, and most importantly, they must be nontoxic.[8]
Because more effective and less toxic radioprotective substances could not be obtained from synthetic compounds, researchers had to focus on assessing the radioprotective potential of natural products.[9] Therefore, worldwide research is underway on radioprotective drugs that do not cause cumulative or irreversible toxicity, provide effective long-term protection, remain stable for many years with long shelf life, and have all the essentials of an ideal radioprotective drug.[10]
Natural Radioprotectors Natural radiation protectors are plant compounds that protect normal (noncancerous) cells from damage from radiation therapy. Natural herbal products are nontoxic with proven therapeutic benefits and have been used to treat various diseases. Of the 1144 new drugs developed in the last 25 years, about 60% come from natural resources. To date, approximately 74 plant products have been tested for their radioprotective potential in a variety of in vitro and in vivo studies. Among them a few plants extract with their mode of action as a radio protector are mentioned in [Table 1]. The use of herbs and diet modulators, along with improved radiation to sensitize tumor cells with radiation, protected normal cells from radiation.[8],[105]
Table 1: List of various plants extract with their mode of action as a radioprotector Need for the Natural Radioprotectors Radiation protectors are drugs or chemicals designed to reduce radiation damage in the human body, damaging IR such as gamma rays, X-rays, cosmic rays, and radiation from radionuclides such as uranium, strontium-90, thorium, cesium-137, radium, and radon. Therefore, radiation oncologists and biologists must research and develop pharmaceutically dynamic, efficient, nontoxic, effective, and easy-to-use radiation protectors to protect humans from this dangerous and destructive IR. An effective radiation protector must have the following characteristics: (i) In most tissues and organs, it provides comprehensive protection against the harmful effects of radiation with minimal side effects, (ii) It should have a long shelf life and be stable, and can easily be administered orally or intramuscularly, (iii) It should be accessible, economically feasible, and compatible with a wide variety of drugs during clinical treatment, (iv) Should be used in recommended doses during a wide range of available, economically viable, and clinical therapies that should be capable enough to reach the target organ and cross the blood-brain barrier, (v) In the event of an emergency, its effect should last for a long time.[9]
Therefore, it can be said that the ideal radiation protector should be nontoxic, and, conversely, able to provide a high degree of protection to normal cells with minimal protection against tumor cells. Failure to develop efficient, effective, low-cost, low-toxic, or nontoxic radioprotectors has led researchers around the world to focus on natural products with radioactive protection potential. Natural herbal products have long been used to treat a wide variety of human diseases, and according to recent databases, about 400,000 medicines from natural sources have been reported.[11]
The detailed descriptions of a few pure form of natural radioprotectors are as follows.
Apigenin
Apigenin (40, 5,7-trihydroxyflavone) is among the most abundant flavonoids and is found in large amounts in the leaves and stems of many fruits and vegetables, including black pepper, Chinese cabbage, broccoli, French peas, garlic, celery, tomato, guava, and onion. It is also found in drinks such as tea and wine produced from plant sources. Apigenin significantly reduces the frequency of IR-induced micronuclei. Furthermore, pre-IR treatment of Apigenin significantly reduces DNA damage in irradiated human peripheral blood lymphocytes, suggesting that Apigenin protects lymphocytes from IR-induced cytogenetic changes.[12]
Bergenin
Bergenin is isolated from the Caesalpinia digyn root extract. These compounds activate various signaling pathways such as ERK1/2, MAP kinase, and SAPK/JNK pathway and induce the production of tumor necrosis factor alpha, nitric oxide, and interleukin (IL-12) in infected macrophages. Bergenin is a hydrolyzable tannin derivative with anti-liver toxicity, anti-ulcer, anti-HIV, anti-arrhythmia, anti-malarial, anti-inflammatory, neuroprotective, and immunomodulatory effects.[13] Bergenin efficiently guards the cells against DNA damage, and its hydroxyl radical scavenging activity is considered important to protect against this DNA damage.[14]
Caffeine
Methylxanthine derivatives caffeine has also shown protective activity against IR damage.[15] Caffeine reduces infrared-induced skin damage associated with radiation therapy and provided radiation therapy for infrared-induced injuries.[16] It has been shown to have radioprotective properties on the mouse BM chromosome before and after systemic IR administration.[17]
Caffeine has both anti-inflammatory and antioxidant properties,[18] which may enhance its protective effect against IR-induced damage. In particular, caffeine purifies hydroxyl radicals[15] and competes with oxygen for IR electronic electrons. Furthermore, caffeine restores the normal cell cycle after IR-induced arrest in the G2 phase of the mouse embryo, and this effect depends on protein synthesis. Finally, caffeine has been shown to reduce UV-induced proteins in melanoma cells.[19]
Chlorogenic Acid and Quinic Acid Chlorogenic acid (5-O-caffeinoquinic acid) is an ester form of caffeic acid and quinic acid and belongs to the group of hydroxycinic acid.[20] Chlorogenic acid is an essential polyphenol extracted from a plant that is abundant in coffee beans and fruits.[21] Quinic acid (1, 3, 4, 5-tetrahydroxyclohexanecarboxylic acid) is a polyphenol that occurs naturally in cocoa beans, wine, coffee, and fruits and can be chemically synthesized from chlorogenic acid. Coffee beans are the major source of chlorogenic and quinic acid.[20] In one study, alkaline comet tests showed that quinic and chlorogenic acids protect against IR-induced DNA damage, indicating significant radiation-protective effects of these compounds.[22] Coniferyl aldehyde and confederal alcohol were isolated from the shells of Eucommia ulmoides oliver and have been shown to induce heat shock transcription factor 1 (HSF1) and protect against IR damage. Simultaneous exposure of cells normal to CA and IR or the chemotherapy drug paclitaxel suggests a protective effect of CA that depends on HSF1 Ser326 phosphorylation. Furthermore, CA in mice inhibited IR-induced BM cell depletion and IR-related increase in terminal deoxynucleotide transferase, which is a DuP NP and labeling (TUNEL) positive BM cell. Studies using the A549 orthotopic lung tumor model have shown that CA does not affect IR-induced lung tumor nodule proliferation while normal lung tissue is protected from radiation. Taken together, these studies suggest that CA can be used to induce HSF1 and protect normal cells from damage caused by IR and/or chemotherapeutic agents.[23]
Delphinidin Delphinidin; an anthocyanidin agent, has potent anti-inflammatory and antioxidant effects in other diverse biological activities.[28] It is found abundantly in pigmented vegetables such as carrots, tomatoes, and red onions, as well as fruits such as cranberries and Concord grapes. Among the anthocyanins, delphinidin has the strongest antioxidant activity due to its many hydroxyl radicals.[29] Delfinidine also protects normal tissue from high linear energy-transfer radiation, such as protons.[30] Considering all these it has been reported that delphinidin is an efficient radioprotector.
Epigallocatechin-3-Gallate Epigallocatechin-3-gallate (EGCG) is a major component of polyphenols in green tea and is widely known as a potent free radical scavenger. Studies have shown that EGCG is effective in treating many disorders.[31] In particular, EGCG has been shown to have anti-aging, anti-angiogenic, anti-arthritis, anti-viral, anti-inflammatory, and neuroprotective effects. EGCG has also been reported to increase levels of several antioxidant enzymes, including glutamate-cysteine ligase, superoxide dismutase (SOD), and heme oxygenase-1 (HO1),[19] both in vivo and in vitro. In addition, EGCG can reduce the radiation sensitivity of cellular systems and improve DNA repair activity after catastrophic IR injury. The protective effect of EGCG against ultraviolet rays, which inhibit skin photoaging, has been widely reported. In addition, a mouse study reported that EGCG showed a radioprotective effect against IR-induced lesions measured along with the spleen.[32]
Hesperidin Hesperidin (hesperetin-7-rhamnoglucoside) is a flavone glycoside from the flavonoid family. Hesperidin is the predominant flavonoid in lemons and sweet oranges and has radiation-protective properties due to its anti-inflammatory and antioxidant properties. In particular, it can prevent oxidative stress damage due to IR exposure to lung tissue. In addition, hysteripidin has been shown to protect lymphocytes from genetic damage that occurs in vitro by the radioactive tracer 99 mTc-MIBI.[33] Furthermore, hesperidin inhibited the IR response in mice[34] and showed antioxidant and anti-apoptotic activity in mouse testes damaged by IR.[35]
Lycopene Lycopene is a widespread dietary carotenoid found in red fruits and vegetables such as pink grapes, tomatoes, apricots, pink guava, papayas, and watermelons,[36] and has exhibited significant protective effects against damage induced by radiation. The antioxidant properties of lycopene have been extensively evaluated in vitro and in vivo and are influenced by its ability to collect ROS.[37] Previous reports have also suggested that lycopene can reduce IR damage by removing intact oxygen and releasing free radicals. Lycopene sham significantly reduced micronuclei, eccentric abnormalities, and occurrence in irradiated human lymphocytes and rat hepatocytes. Lipid peroxidation by IR was reduced by lycopene pretreatment and increased the activity of antioxidant enzymes, including SOD, antacid, and glutathione peroxidase.[38]
N-Acetyl Tryptophan Glucopyranoside The bacterial secondary metabolite, N-acetyl-tryptophan glycoside (NATG), was purified from the radiolabeled bacterium Bacillus subtilis. NATG pretends to have radiation protection by increasing the cytoprotective cytokines interferon-c, IL-17A, and IL-12 to prevent IR-induced apoptosis.[39] Inhibition of NATG has also been shown to protect J774A.1 macrophages from IR-induced DNA damage[40] along with increased antioxidant activity against IR-induced damage in murine macrophages.[41]
Sesamol Sesamol (3,4-methylenedioxyphenol), a component of sesame and sesame oil, is a natural phenolic antioxidant. Seasamol has strong ROS absorption and antioxidant properties and can protect against IR-induced DNA damage in human lymphocytes.[42] Furthermore, cisamol significantly reduces IR-induced DNA damage in the mouse hematopoietic system,[43] and reduces the genotoxicity of bone marrow cells.[44] Further, it protects the gastrointestinal and hematopoietic systems against IR-induced injury in mice.[45] The radioprotective effect of sesamol is affected by ROS purification and enhancing DNA repair activity.[46]
Lutein Lutein, a carotenoid that is devoid of any provitamin A activity, contains β-and ε-ionones. It is one of several carotenoids that are found naturally in plants such as egg yolk, green leafy vegetables (spinach, cabbage), animal fat, and corn. Lutein is found in both the macula and lens of the human eye and performs a dual function in both tissues by acting as a powerful antioxidant, and filtering high-energy blue light thus protect the eye from oxidative stress. Preradiation treatment with lutein has been reported to reduce radiation risk while reducing total antioxidant capacity, hematologic parameters, antioxidant enzyme levels, and maintaining MDA and GSH.[47] In addition, the presence of β-and ε-hydroxyl motif can increase antioxidant levels and overall antioxidant capacity, protecting and enhancing membrane stabilization and thrombolytic potential,[48] antioxidant enzyme activity, thereby increasing its radiation-protective properties.[47]
Conclusion and Future Directions Protecting humans and animals from the effects of IR radiation is an important issue in radiobiology and medicine. The work outlined here suggests that there are many potential radiation protectors with different purposes and mechanisms. Radioprotective agents inhibit or destroy free radicals, activate enzymes involved in DNA breakdown repair, stimulate the hematopoietic and immune systems, or interact with proteins in signaling and apoptosis pathways, resulting in IR-Induced trauma and/or IR-related syndromes. These radiation preservatives include both synthetic compounds and natural products. However, naturally occurring compounds have significant advantages for use in radiation protection. The main advantage of using naturally found compounds is that they have increased safety compared to synthetic compounds. In addition, natural products are effective in treating symptoms similar to radiation syndrome.[47] Studies investigating these compounds as a novel approach to radiation protection have shown the efficacy of herbal compounds. Cellular and animal model research suggests that radioprotective agents can reduce DNA damage through various mechanisms; however, most of the available information in the literature suggest that Free radical scavenging role and free radical induction role of natural radio protectors.[48] Further research is warranted to determine the radioprotector has an efficient therapeutic regime. In addition, the direction for future strategies relevant to the development of radio protectors is also addressed as a pivotal step for successful identification of radio protectors by drug discovery process. This emphasizes the need for not new on the strategies for the development of novel radio protectors for drug development.[47]
Financial support and sponsorship
We'd like to thank our RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates, for their encouragement and support.
Conflicts of interest
There are no conflicts of interest.
References 
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