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REVIEW Radioprotectors – the Evergreen Topic by Vesna S. Kuntic´ a ), Miroslava B. Stankovic´ b ), Zorica B. Vujic´ a ), Jasmina S. Brboric´ a ), and Snezˇana M. Uskokovic´-Markovic´* a ) a
) University of Belgrade – Faculty of Pharmacy, Vojvode Stepe 450, P.O. Box 146, 11221 Belgrade, Serbia (phone: þ 381-11-39-51-238; fax: þ 381-11-39-72-840; e-mail:
[email protected]) b ) Nuclear Facilities of Serbia, Mike Petrovic´a Alasa 12 – 14, Vincˇa, P.O. Box 4, 11000 Belgrade, Serbia
To protect organisms from ionizing radiation (IR), and to reduce morbidity or mortality, various agents, called radioprotectors, have been utilized. Because radiation-induced cellular damage is attributed primarily to the harmful effects of free radicals, molecules with radical-scavenging properties are particularly promising as radioprotectors. Early development of such agents focused on thiol synthetic compounds, known as WR protectors, but only amifostine (WR-2721) has been used in clinical trials as an officially approved radioprotector. Besides thiol compounds, various compounds with different chemical structure were investigated, but an ideal radioprotector has not been found yet. Plants and natural products have been evaluated as promising sources of radioprotectors because of their low toxicity, although they exhibit an inferior protection level compared to synthetic thiol compounds. Active plant constituents seem to exert the radioprotection through antioxidant and free radical-scavenging activities. Our research established that plants containing polyphenolic compounds (raspberry, blueberry, strawberry, grape, etc.) exhibit antioxidative activities and protect genetic material from IR.
Contents 1. Introduction 2. The Effects of Ionizing Radiation on Cell 3. Mechanism of Radioprotectors Action 4. Radioprotectors 4.1. Synthetic Radioprotectors 4.1.1. Amifostine 4.1.2. Non-Thiol Radioprotectors 4.2. Natural Origin Radioprotectors 4.3. Phyto-Radioprotectors 4.3.1 Phyto-Radioprotectors from the Serbia Region 5. Conclusions
1. Introduction. – Ionizing radiation (IR) is one of the strongest mutagens in the surroundings. People may be exposed to IR during radiotherapy or following exposure to radionuclides in nuclear medicine. IR have always remained a part of our 2013 Verlag Helvetica Chimica Acta AG, Zrich
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environment; it is present in the atmosphere as background radiation emitted by the radioactive elements present in earth crust, as radon (54%) and as cosmic rays (8%) [1]. Exposure to IR could lead to varied effects ranging from point mutations to severe damage to the genetic material, depending on the dose of radiation [2]. With respect to the potential application of IR in medical practices and also potential accidental exposure to radiation (e.g., industrial nuclear accident), the investigation of radioprotectors – compounds which can protect organisms from harmful effects of IR – is of great importance. Radioprotectors could be defined as any agent applied before, during or after radiation which protects from radiation caused damage [3] [4]. The aim of this review article is to provide a survey of novel literature data about synthetic, natural origin, and phyto-radioprotectors, as well as the mechanism of their protective action. Additionally, we would like to offer a personal account on the development of the field through a retrospective of our own research that covers extracts of some plants from the Western Balkan. 2. The Effects of IR on Cell. – IR, either particles (electrons, positrons, neutrons, aparticles, deuterons), or electromagnetic waves (g-rays, X-rays), have enough energy to dislocate electrons from the atoms of the matter they fall on, hence ionizing them. In a living cell, IR alters the chemical structure of cell constituents at a level dependent on the dose and the duration of exposure, as well as on the tissue sensitivity [2]. According to literature, the biological effects of IR in cell can be direct (targets effects) and indirect (no targets effects) [2] [5] (Fig.). Directly, IR damages the macromolecules,
Figure. Effects of ionizing radiation on a living cell
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i.e., proteins, lipids, but DNA is known to be the prime target of IR-induced damage in the cell. It provokes an array of changes ranging from mutations, base lesions, crosslinking, and single and double stranded breaks. Indirectly, IR collides with H2O molecules within the cell, causing spontaneous generation of free-radical species (reactive oxygen species (ROS)): OH . , H . , eaq , H3O þ, and very toxic, H2O2 [6]. ROS Damage macromolecules afterwards, which could even lead to the death of the cell itself [7]. Cell-reparing enzyme systems (superoxide dismutase, glutathione peroxidase, and catalase), having been formed through evolution to protect the integrity and the accuracy of hereditary material, usually cannot fix such hard lesions and repair DNA [8]. The damages are usually fixed wrongly, which leads to new mistakes in the DNA replication process, i.e. chromosomal aberrations. Chromosome aberrations are the final result of the whole series of complex biochemical reactions and probably represent cytological manifestation of unsuccessful attempts of the cell to repair and eliminate hereditary-material primary damage by molecule interventions. 3. Mechanism of Radioprotection. – People can protect themselves against IR by using compounds that prevent indirect action, and repair direct or indirect damages in the cells after IR exposure. In general, radioprotective agents suppress reactivecompound formation (free-radical scavengers), detoxify radiation-induced species, target stabilization of vital biomolecules, and enhance the repair and recovery processes. Radioprotectors can also act as immunomodulators, i.e., they stimulate the proliferation of hematopoietic and immunopoietic stem cells [9]. In relation to the IR exposure (Fig.), radioprotective agents can be classified as chemical radioprotectors/ prophylactic preparations, mitigators, and therapeutic preparations [5] [9]. Prophylactic formulations, also known as classical radioprotectors, are used before IR exposure to prevent tissue damage. This class of radioprotectors belongs to compounds with thiol (sulfhydryl) groups and/or compounds with antioxidant properties [4] [5]. Mitigators are applied during or after IR exposure, but before manifestation of radiation symptoms, with the aim to minimize toxicity, and prevent or reduce the negative effects of radiation on cells/tissues [5]. This class of compounds includes chelating agents (chelators) and blocking agents, such as KI, which protects the thyroid gland from radioactive isotope iodine-131, by preventing its accumulation in the thyroid [10]. Therapeutic preparations are applied after radiation exposure, in the cure treatment and healing from the acute radiation syndrome and delayed effects of radiation exposure, such as fibrosis, vascular damages, and numerous damages of organs. 4. Radioprotectors. – 4.1. Synthetic Radioprotectors. For the very first in vivo researches of potential radioprotectors, more than a half century ago, the amino acid cysteine, which contains a SH group, was used [11]. From 1957, when the US Military started developing radioprotective agents, in the research community known as WR (WR, radiation weighting factor) protectors, over 4,400 compounds with aminothiol group were synthesized [12]. WR Agents structurally differ in the length of aminoalkyl groups, by the Me-group presence/absence on the terminus, and/or by the presence of a OH group on the alkyl chain [9]. The most prominent compound in this class is amifostine.
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4.1.1. Amifostine (WR-2721). Amifostine is an organic thiophosphate prodrug, the analog of cysteamine. Chemically, it is the ester of thiol and phosphoric acid, named 2[(3-aminopropyl)amino]ethanethiol dihydrogenphosphate (aminopropylaminoethylthiophosphate) [13]. Amifostine radioprotection is realized through dephosphorylation by the enzyme alkaline phosphatase to form a free thiol that represents its active metabolite named WR-1065. Due to the much higher content of alkaline phosphatase in a healthy than in a tumor cell and higher pH values, WR-1065 accumulates in healthy cells, making its concentration a few hundred times higher. WR-1065 protects healthy cells primarily by neutralizing and elimination of ROS, and also helps recovery of damaged DNA by donating hydrogen [14] [15]. Amifostine is the only radioprotector approved by the Food and Drug Administration (FDA) for use in human medicine [16]. 4.1.2. Non-Thiol Radioprotectors. Besides compounds with SH groups, in the last five decades a huge number of compounds of the classes aminosulfides, thiourea derivatives, thiosulfates, thiophosphates, diethyldithiocarbamates, and thiazoles were synthesized and examined, including some biogenic amines and their derivatives [17 – 19]. Radioprotectors are mainly synthesized in the form of esters with phosphoric acid (prodrug) to achieve better solubility in H2O [20]. Nitroxides are the most promising, low-molecular-weight compounds, which represent stable organic free radicals. Nitroxides act as superoxide dismutase mimics, defending cells against oxidative stress, inhibit lipid peroxidation, and prevent disruption of the DNA helix [21]. Nitroxides can also modulate the redox state of the cell by participating in oxidation/reduction reactions [22]. Tempol ( ¼ 4-hydroxy2,2,6,6-tetramethylpiperidine-1-oxyl (in literature cited as: 4-hydroxy-TEMPO; Tanol; TMPN; 4-oxypiperidol; nitroxyl 2; HyTEMPO) is the leading heterocyclic compound of this radioprotector class [23 – 25]. Compounds with the bis-benzimidazole group, the most prominent representative Hoechst-33342, 2’-[4-ethoxyphenyl]-5-[4-methylpiperazin-1-yl]-2,5’-bis[1H-benzimidazole] trihydrochloride, also shows a radioprotective effect, the mechanism of which involves donation of an electron from the ligand to damaged DNA [26] [27]. In recent years, there have been examinations of fullerenes and their derivatives for immunomodulatory, neuroprotective, and radioprotective effects [28], but the potential biomedical application is limited because of their extremely poor solubility in polar solvents. Fullerenol, C60(OH)24 , is a H2O-soluble compound with improved chemical properties. The free-radical scavenger property of this compound is based on radical addition reaction between a hydroxyl radical (HO . ) and double bonds in fullerenol [29]. The results of experiments on animals show that fullerenol has a significant radioprotective effect, which is comparable to that of the standard radioprotector amifostine [28]. The promising radioprotectors are drugs from the class of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, well known as statins. In recent years, it has been confirmed that statins (lovastatin, simvastatin, pravastatin) have the potential to protect human endothelial cells from IR, reduce the response to acute inflammation, and show the antifibrous effects [30] [31]. The application of some cardiovascular drugs, angiotensin-converting enzyme inhibitors (ACE inhibitors), such as captopril, ramipril, and perindopril, in the
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treatment and prevention of damages caused by the radiation during radiotherapy has been investigated [32] [33]. The combined synergistic therapy of calcium antagonists, i.e., diltiazem, nimodipine, and nifedipine (which inhibit calcium influx through plasma membrane, thus influencing several cellular functions), with zinc salts (Zn aspartate) results in protection of healthy tissue in tumor therapy [34]. The synthetic radioprotective agents and their proposed acting mechanisms are compiled in Table 1. 4.2. Radioprotectors of Natural Origin. Contrary to the majority of synthetic radioprotectors which are not suitable for human application because of the high toxicity and severe side-effects [47], compounds of natural origin are less toxic and do not exhibit serious side-effects. Below, the most prominent radioprotectors are shortly presented. b-Glucans and polysaccharide ginsan have been known to have multiple immunomodulatory effects but also confer strong radioprotection. This class of compounds stimulates endogenous production of cytokine (interleukins IL-1 and IL-6), and increase the number of bone marrow cells, circulating neutrophils, lymphocytes, and platelets in irradiated mice [35]. A hormone, 5-androstenediol, produced by the human adrenal cortex, is also examined as a potential radioprotector which stimulates myelopoiesis, and increases the number of circulating neutrophils and platelets, but not erythrocytes [37] [48]. Although it has a potent radioprotective effect and low toxicity, there are also problems with its application due to low oral efficiency and local inflammatory response at the site of injection [49]. The application of oxymetholone (steroid with androgenic/ anabolic effect) offers a good protective effect, since it can be administered orally. Furthermore, oxymetholone has broad therapeutic index and low toxicity [38]. The compounds from lipopolysaccharide [39], prostaglandin [40], and hormone classes [50], as significant natural antioxidants, have also been subjected to significant tests. The considerable radioprotective effect is observed of vitamins A, C, and E [41] [51]. There have also been confirmed radioprotective effects of vitamin E (atocopherol) and its H2O-soluble derivative tocopherol monoglucoside [52], as well as a-tocopherol succinate, which induces the formation of two cytokines that stimulate platelet formation [42]. There are numerous studies that confirmed the radioprotective effect of melatonin ( ¼ N-acetyl-5-methoxytryptamine), since it is a scavenger of ROS, primarily of HO . and peroxyl radicals, as well as peroxynitrite anions [43]. There are some attempts of combined therapy of amifostine and melatonin, as well as calcium antagonists (nimodipine) to increase the radioprotective action and decrease the toxicity [53]. The radioprotective agents of natural origin and their proposed acting mechanism are collected in Table 1. 4.3. Phyto-Radioprotectors. Numerous of plants and herbs, as well as the compounds isolated from plants, are very effective radioprotectors [44]. Unlike the synthetic compounds, herbal products are nontoxic, without harmful effects to human health, inexpensive, and are generally administered orally [45]. Considering the described radioprotective mechanisms, it can be concluded that each plant that has the antioxidant, anti-inflammatory, antimicrobial, or immunomodulatory properties will also display radioprotective properties [36].
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Table 1. Synthetic and Natural Radioprotective Agents and Their Acting Mechanisms Radioprotectors/Mitigators and Therapeutics
Radioprotective Effect/Proposed Mechanism of Action/Use
Ref.
Chelators: Chelating with transuranium radionuclides (Pu, Diethylenetriaminepentaacetate ( DTPA ) Am, Cm)
[4]
Sulfhydryl compounds: Free-radical scavenging Cysteine, cysteamine, glutathione, amino- Donation of H-atom ethyl-isothiourea, amifostine (WR 2721) Hypoxia in cells and tissues and other WR compounds
[5] [14] [15]
Metalloelements and metallothionine: Bismuth subnitrate
Protection of hematopoietic system from lethal effects of IR; induction of metallothionine synthesis in bone marrow cells
[9]
Selenium compounds: (selenomethionine, sodium selenite)
Preventing mutagenic changes induced by IR
[9]
Cytoprotective agents approved by FDA: Mesna, dexrazoxane, and amifostin
Reduced toxicity of chemotherapeutic drugs; [9] decrease of urothelial toxicity and nephrotoxicity
Potassium iodide (KI )
Protective measure to reduce thyroid radioiodine [10] uptake
Nitroxides: Tempol, tempol-H, tempace, troxyl
Superoxide dismutase mimics Free-radical scavenging
[23] [25]
DNA Binding ligands: Bis-benzimidazoles: Hoechst 33342
Electron transfer; free-radical scavenging
[26]
Fullerenes: Fullerenol C60(OH)24
Free-radical scavenging in biological systems
[28] [29]
HMG-CoA Reductase inhibitors ( Statins): Mitigation of radiation enteropathy, pulmonary Lovastatin, simvastatin, pravastatin fibrosis ACE Inhibitors: Captopril, enalapril, ramipril, perindopril ACE Receptor antagonist: Penicillamine, pentoxyfylline
[31]
Inhibition of angiotensin II production; suppres- [32] sion of proliferation; prevention of the development of radiation-induced late effects (including kidney and lung damages); suppression of chronic oxidative stress
Ca-Antagonist and Zn salts: Inhibition calcium influx through plasma memSynergistic combinations (diltiazem, nife- brane dipine, nitrendipine, nimodipine) and Zn salts (Zn aspartate)
[34]
Immunomodulators: g-Interferon, polysaccharides Steroids: 5-Androstendiol, oxymetholone
Increased production of cytokines Immune stimulation Myelopoiesis stimulation and enhancement of circulating neutrophil and platelet numbers
[35] [36] [37] [38]
Lipopolysaccharides and prostaglandins: Misoprostol
Prostaglandin synthesis; DNA repair; elevated levels of cyclic AMP
[39] [40]
Antioxidants: Free-radical scavenging [42] [43] Vitamin A, C, and E (a-tocopherol mon- Inhibition of chromosomal aberrations and creaoglucoside); melatonin tion of micronuclei in lymphocytes Plant extracts and isolated compounds [44 – 46]
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Table 1 (cont.) Radioprotectors/Mitigators and Therapeutics
Radioprotective Effect/Proposed Mechanism of Action/Use
Ref.
Removal of the primary and secondary ROS; antioxidant activity; inhibition of lipid peroxidation; protective effect against DNA chain termination; improved hematopoietic recovery
The radioprotective effect of plants on the humans are generally tested on the peripheral blood lymphocytes as models, where the main criterion of efficiency is the reduction of IR damage of the cells which are in contact with the preparation to be examined [54] [55]. There were also tests on rodents, which displayed a significantly higher survival rate of the animals that received the potential radioprotector than animals in the control group, after X- or g-rays exposure [56]. Besides these studies, there are a few studies assessing the radioprotective effects of phytochemicals in human volunteers for reducing the genetic side-effects caused by IR [57]. Various plant species have been examined as potential radioprotectors, since the entire plant kingdom, including legumes, nuts, seeds, and grains, represents a source of antioxidants (it is assumed that there are 8,000 antioxidants) [58]. Although it is not possible to list all the plants studied so far and their active ingredients, many of which are specifically restricted to some areas, we will mention only a few: extracts from citrus fruits [59], as well as their main active ingredient, hesperidin [55] [60] [61], green tea [62], ginkgo extract [63], extract of grape, i.e., wine [64], mint tea [65], soy products [66], onion [67], and ginger root [68]. In the review article of Nambair et al., the effects of various phytochemicals (curcumin, parthenolide, genistein, gossypol, ellagic acid, withaferin, plumbagin, and resveratrol) on IR were compiled [2]. Since peppermint is widely known to relieve digestive ailments and is a popular remedy in the various traditional and folk medicines all over the world, we refer to the review article of Baliga and Rao about radioprotective potential of aromatic herb mint, Mentha piperita and M. arvensis, where the authors emphasized their protection of vital organs and discussed their radioprotective mechanism in detail [69]. The largest number of potential radioprotectors consist of polyphenolic compounds and belong to the class of flavonoids in the broad sense [46]. For the time being, more than 5,000 different flavonoids were identified and characterized from various plants, and this number is constantly increasing [70]. Depending on the oxidation pattern of the heterocyclic ring, flavonoids are usually classified as flavones, flavanonols, flavonols, flavanones, or isoflavones. Another group of flavonoids, in the broad sense, include anthocyanidins, proanthocyanidins, calchones, and catechins [46]. Much of the attention focused on flavonoid arises from the results of epidemiological studies that suggest high fruit and vegetable consumption is associated with a decreased risk of several types of cancer including breast, colon, lung, larynx, pancreas, oral, and prostate cancers [71]. These results evidenced protective effects of flavonoids, and, together with their potent antioxidative and free radical-scavenging activities observed in in vitro studies, have increased the interest in the use of flavonoids for their potential health benefits. Thus, flavonoids are referred to as nutraceuticals [72].
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4.3.1. Phyto-Radioprotectors from the Serbian Region. In our research, we investigated the extracts/seeds of some plants from the Serbian region (raspberries, blackberries, blueberries, currants, grapes, stepe fannel, and horsetail), as compiled in Table 2 [73 – 79]. The results showed that all of the above mentioned plants exhibit significant radioprotective properties. For example, our studies have shown that berries (such as raspberry, blackberry, and currant), i.e., their phenolic compounds, affect the reduction of DNA damage by preventing the formation of free radicals [73] [76] [79]. However, more important in blueberries is the presence of ellagic acid that promotes proper repair of DNA damaged by irradiation [73]. Ellacgic acid also affects the cancer cells that multiply rapidly by slowing down and, in certain concentration, completely stopping its division. This acid causes apoptosis of cancer cells and blocks DNA damage, i.e., it has antimutagenic effects [76]. The extract of five species of horsetail (Equisetum arvense), which grows in Serbia, has also been investigated. Compounds from horsetail (besides alkaloids, flavonoids, glycosides, b-carotene, vitamin C, macro- and micronutrients, horsetail also contains silicon acid) strongly inhibit lipid peroxidation, protect the structural proteins of the blood vessels, and preserve their selective permeability [74] [79]. The antioxidant compounds of grape have beneficial effect on irradiated cells, since they reduce the level of reactive free radicals and repair DNA damaged by radiation [75]. The 17 identified compounds comprised gallic and protocatechuic acid, catetchin and epicatechin monomers, procyanidin oligomers, and procyanidin gallates. Recent studies demonstrated that grape may be effective in the prevention of oxidative lymphocyte damage by ROS. Furthermore, the antioxidant properties of red wine inhibit the development of many diseases due to its ability to keep the balance of mitochondrial redox potential. Two glasses of red wine per day in the diet increased the flavonoid content by 40%, which exceeds the effects of good free-radical scavengers [75]. The results from the study of the protective effects of Ononidis radix confirmed that the compounds isolated from this plant showed strong antioxidant and antimutagenic effects, thus reducing the level of reactive free radicals in the cell, leading to a positive physiological effect [74] [78]. 5. Conclusions. – The development of effective radioprotectors is of great importance in view of their potential application during both planned (radiotherapy) and unplanned radiation exposure (nuclear accidents, natural background radiation emanating from the earth, or other sources). Although numerous compounds were tested for this purpose, amifostine is the only radioprotector that has been officially approved for human use. Since this drug shows serious side-effects, medical opinions concerning its use differ [80] [81]. For that reason, the focus for the new radioprotectors moves towards herbal products, which are nontoxic, inexpensive, and easy to administer. A number of medicinal plants evaluated for their radioprotective afficiencies has displayed protective effects against the damaging effects of IR. All plants with antioxidant properties, i.e., whose active ingredients are free-radical capturers, are potential radioprotectors, but their protective effect can be confirmed only after experiments on human lymphocyte and rodents.
Protective properties
Ref.
[75]
[76]
Polyphenolic compounds: flavones, Antioxidant, radioprotective flavonols, isoflavones, anthocyanins, anticancer, anti-inflammatory effects catechins, procyanidol Ellagic acid, vitamin C, ellagitannin Antioxidant, anticancer, and antimutagenic effects. Ellagic components, salicylic acid acid causes apoptosis in cancer cell.
Vitis vinefera (Grapes and wine)
Rubus idaeus ( Raspberry)
[74]
Antioxidant, radioprotective, Dicaffeoyl meso-tartaric acid, saponins, polyphenolic compounds, cytotoxic effects silicic acid
Antioxidant, anticancer, [73] antimutagenic, antiseptic effects
Equisetum arvense ( Horsetail)
Compounds Quercetin, organic iron, potassium, calcium, phosphorus, vitamins B1, B2, C, PP
Structural formulae
Rubus fruticosus ( Blackberry)
Plants/Herbs
Table 2. Plants from Serbian Region with Antioxidative and Radioprotective Properties
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Ononin, onospin, tannins, essential oil
Vitamin C, carotene, vitamin K
Ononidis radix ( Rabbit thorn)
Ribes rubrum (Currant)
Compounds Phellopterin, coumarine, quinone
Structural formulae
Seseli annuum ( Steppe fennel)
Plants/Herbs
Table 2 (cont.)
Antioxidant, anticancer, antimutagenic effects
[79]
[78]
[77]
Antioxidant, anticancer, antimutagenic effects
Antioxidant, radioprotective effects
Ref.
Protective properties
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The authors gratefully acknowledge the financial support from the Ministry of Science and Environment of the Republic of Serbia, grants No. 172041 and 172043.
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