|Year : 2016 | Volume
| Issue : 4 | Page : 1234-1242
Prophylactic role of some plants and phytochemicals against radio-genotoxicity in human lymphocytes
Mohsen Cheki1, Ehsan Mihandoost2, Alireza Shirazi1, Aziz Mahmoudzadeh3
1 Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
2 Department of Radiology and Medical Physics, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran
3 Novin Medical Radiation Institute, Tehran, Iran
|Date of Web Publication||7-Feb-2017|
Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran University of Medical Sciences, Keshavarz Boulevard, Poursina Avenue, Tehran
Source of Support: None, Conflict of Interest: None
Genotoxicity in lymphocytes of cancer patients undergoing radiotherapy can lead to lymphocytopenia. Lymphocytopenia induced by radiotherapy is one of the most unfavorable prognostic biological markers in cancer patients, since it has been accepted to be associated with poor prognosis in terms of both survival time and response to cancer therapy. Therefore, reduction in lymphocytopenia may increase treatment efficiency. Research endeavors with synthetic radioprotectors in the past have met with little success primarily due to toxicity-related problems. These disadvantages have led to interest on the use of some plants and phytochemicals as radioprotector. The aim of this paper is to review protective role of some plants and phytochemicals against genotoxicity-induced by ionizing radiation in human blood lymphocytes. Therefore, current review may help the future researches to decrease lymphocytopenia in radiotherapeutic clinical trials.
Keywords: Genotoxicity, human lymphocytes, ionizing radiation, phytochemicals, plants
|How to cite this article:|
Cheki M, Mihandoost E, Shirazi A, Mahmoudzadeh A. Prophylactic role of some plants and phytochemicals against radio-genotoxicity in human lymphocytes. J Can Res Ther 2016;12:1234-42
|How to cite this URL:|
Cheki M, Mihandoost E, Shirazi A, Mahmoudzadeh A. Prophylactic role of some plants and phytochemicals against radio-genotoxicity in human lymphocytes. J Can Res Ther [serial online] 2016 [cited 2018 Jun 18];12:1234-42. Available from: http://www.cancerjournal.net/text.asp?2016/12/4/1234/172131
| > Introduction|| |
Exposure of living systems to ionizing radiation (IR) leads to the formation of reactive oxygen species (ROS) and reactive nitrogen species. These reactive species impose damage to the various bio-macromolecules such as DNA, lipids, and proteins present in the cell., It is known that human lymphocytes, the most important white blood cells, are very sensitive to IR. It has been reported that IR caused DNA damage in human peripheral blood lymphocytes (HPBLs) which can lead to cell death or genomic instability., The decrease in peripheral leukocyte count, particularly lymphocyte, following radiation therapy (RT) has been widely reported. Lymphocytopenia represents one of the most evident side effects of RT, particularly in the case of pelvis cancer, which negatively influence the efficacy of RT.,,,,, Thus, lymphocytopenia decrement may result in an effective treatment. Radioprotectors are compounds that have the ability to decrease the biological effects of IR on normal cells and tissues, including lethality, mutagenicity, and carcinogenicity. Although radioprotectors may provide the opportunity to decrease harmful effects of RT, few radioprotective agents are in clinical use primarily due to undesirable side effects such as hypotension, vomiting, nausea, sneezing, hot flashes, mild somnolence, and hypocalcemia., Therefore, the search for radioprotectors with less toxicity must continue with increased excitement for find new agents that can protect against radiation-induced damage in healthy organs. Extensive studies of plants and phytochemicals have shown that these compounds have protective effects against radiation damages with fewer side effects., This review emphasizes on the state of knowledge about plants and phytochemicals were used in order to reduce genotoxicity induced by IR in HPBL.
| > Critical Target of Radiation|| |
The main target of IR is DNA, a macromolecule with well-known double helix structure, consisting of two strands held together by hydrogen bonds between the bases. IR causes DNA damage via two different ways, namely indirect and direct effects. The indirect effect refers to the interaction of hydroxyl radicals from water radiolysis with the local molecules surrounding and/or on the DNA, whereas the direct effects result from the ionizations that create sites of radical cations, radical anions, and excitations.,, Upon the interaction of IR and cells, more than half (about 60%) of the IR energy deposited in the cell is initially absorbed by water in the cytosol because the eukaryotic cell contains 70–80% water molecules, the majority of which are found in the cytosol and thus form the hydration layers of the cellular structural components and macromolecules. Subsequently combined with the indirect effect of radicals resulting from water radiolysis in the cytoplasm, the remaining energy (<40%) may significantly damage DNA in the nuclei.,
IR induces a wide variety of lesions that can cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Single strand breaks (SSBs) are of little biological significance as regards cell killing, as they are readily repaired using the opposite stand as a template. However, if the repair is incorrect (mispair), it may result in mutation. Double strand breaks (DSBs) are thought to be the most harmful of IR-induced lesions and occur when breaks in the two strands are opposite to one another, or separated by only a few base pairs. IR also induces other forms of DNA damage including cross-links, oxidative base modification, and clustered base damage.,, The numbers of DNA lesions per cell that are reported immediately after a radiation dose of 1 Gy have been estimated to be approximately >1000 base damage, 1000 SSBs, 40 DSBs, 20 DNA–DNA cross-links, 150 DNA–protein cross-links, and 160–320 non-DSB clustered DNA damage.,, Failure to repair DNA damage can have deleterious outcomes such cell death or genomic instability., Genomic instability has been studied by several indices, including analyses of chromosomal rearrangements and aberrations, gene amplification, aneuploidy, micronucleus formation, microsatellite instability, and gene mutations [Figure 1].,, Chromosomal instability is a well-characterized index of genomic instability that can persist for multiple generations after exposure to a range of genotoxic agents in a variety of mammalian cells.,,,, Natarajan et al. indicated that radiation-induced DSBs are mainly responsible for the formation of chromosomal aberrations (CAs). There are essentially three types of aberrations of radiated chromosomes in a mitotic cell namely, dicentric (DC), acentric fragments, and acentric rings, as a result of breakages and exchanges of chromatids. Damages to chromosomes are also demonstrated as micronuclei (MN) in rapidly proliferating cells. DSBs are repaired by either of the two mechanisms; the nonhomologous end joining pathway or homologous recombination pathway.,
|Figure 1: Radio-genotoxicity process and prophylactic role of radioprotectors|
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| > Human Peripheral Blood Lymphocyte: A recommended Target for Bio-Radioprotection Studies|| |
One approach to identify nontoxic and effective radioprotective compounds that can reduce adverse effects of IR are in vitro experiments, using human lymphocytes as a model system, because they are readily available, synchronized in G0, representative of averaged whole body radiation exposure, containing variety of redox, and free radical scavenging systems. In several studies, in vitro and in vivo, experiment on HPBL has been reported as a preferred model to understand the harmful effects of radiation in normal healthy cells. Monitoring of patients under radiotherapy for DNA damage could therefore contribute to the optimization of irradiation conditions and biological dosimetry.,, IR-induced DNA damage can be turned cytogenetic alterations such as CAs, MN, and sister chromatid exchanges (SCEs), interchanges of DNA replication products between sister chromatids at apparently homologous loci., Cytogenetic alterations induced by IR can be observed in HPBL within a few hours of exposure. Their frequency is related to the dose and quality of radiation and can be detected in blood samples taken long after the exposure.,
On the other hand, DNA damage in HPBL can lead to lymphocytopenia in cancer patients undergoing RT. Because of the fundamental role of lymphocytes in suppressing anticancer immunity, RT-induced lymphocytopenia could negatively influence the prognosis of cancer patients and the therapeutic efficacy of RT itself., Multivariate analyses have revealed a significant association between chemo-radiation-related lymphocytopenia and survival., Furthermore, Lissoni et al. demonstrated that pelvic RT-induced lymphocytopenia could negatively influence the efficacy of RT itself and the decline in total lymphocyte number was also significantly greater in patients who had no tumor regression in response to RT. Thus, lymphocytopenia reduction by radioprotectors may result in an improved response to cancer therapy and finally longer survival time. Famotidine is a specific, long-acting histamine H2-receptor antagonist with extensive use in the treatment of peptic ulcers. Experimental studies have shown that famotidine exert radioprotective effects on radiation-induced MN and CAs in HPBL. Razzaghdoust et al. have reported that oral administration of famotidine tablets (40 mg) twice daily, 4 and 3 h before each RT fraction significantly reduced radiation-induced lymphocytopenia in prostate cancer patients. Hence, in vitro and ex vivo assessment of radioprotectors against cytogenetic alterations induced by IR in HPBL will be necessary, before administration of these compounds to cancer patients undergoing RT in order to lymphocytopenia decrement.
| > Ideal Radioprotector|| |
An ideal radioprotector should be readily available, inexpensive, does not have toxic implications in a wide dose range, and have compatibility with the wide range of other drugs that will be available to patients or personnel, shelf-life should be long, easy handling and storage, absence of cumulative effect in repeated administration, orally administered, ability of fast resorption, and distribution in tissue and organs, have a general protective effect on the majority of organs, radiosensitive for tumor cells, efficacy for different types of radiation (X, gamma, electrons and neutrons), efficacy in joined and fraction radiation, act in a wide time-window to render protection, protect all populations at risk, possesses a reasonably good dose reduction factor, and can act through multiple mechanisms.,,
| > Tendency Process to Plants and Phytochemicals as Radioprotector|| |
Advances in radiation sciences, particularly the understanding of radiation effects on biological systems, have paved the way toward the development of radioprotective compounds that can be effectively utilized to achieve protection against the deleterious effects of IR. Research and development on radioprotective drugs started nearly 60 years ago. In 1949, Patt et al. were the first to investigate the radioprotective effect of amino-acid cysteine when exposed to lethal doses of X-rays. For almost three decades, the Walter Reed Army Research Institute synthesized and tested over 4000 compounds in an attempt to find a useful radioprotector, one that would protect against IR without toxic side effects. The most effective compound of this type, originally tested against lethal doses of X-rays and γ-rays in mice, is WR-2721, the common name of which is amifostine. Amifostine selectively protects a broad range of normal tissues, including the oral mucosa, salivary glands, lungs, bone marrow, heart, intestines, and kidneys. Although amifostine was reported to be tolerated well in radiotherapeutic clinical trials, it was later found to have some undesirable side effects. These include hypotension, nausea, vomiting, diarrhoea, hypocalcemia, nephro- and neuro-toxicity, and allergy is the main problem related to use of it in patients and public during exposure to IR.,,,, The most side effects related to amifostine are dose-dependent. The major dose-limiting toxicity of amifostine is transient hypotension. Even at low doses used in RT close monitoring of blood pressure is required. Most patients receiving amifostine with RT require antiemetics., Moreover, amifostine has some disadvantages, such as limited routes of administration, narrow time windows for radioprotection, cost, and limited protection of the central nervous system. Because of the inherent toxicity of chemicals and synthetic agents at their effective radioprotective concentrations, investigators diverted their attention toward plants and phytochemicals as radioprotector. Plants (fruits, vegetables, and medicinal herbs) have been in use in several traditional systems of medicine for several hundreds and even thousands of years for treating various human ailments all over the world since they offer holistic treatment. Several of these plants have been reported to be beneficial for ameliorating free radical-mediated disease conditions in humans such as arthritis, atherosclerosis, cancer, Alzheimer's disease, Parkinson's disease, aging, and inflammatory disorders.,, Phytochemicals, as plant components with discrete bio-activities toward animal biochemistry and metabolism, are being widely examined for their ability to provide health benefits. Research supporting beneficial roles for phytochemicals against cancers, coronary heart disease, diabetes, high blood pressure, inflammation, microbial, viral and parasitic infections, psychotic diseases, spasmodic conditions, and ulcers. Therefore, screening of plants and phytochemicals offers a major focus for new drug discovery. In this way, attention over the past 20 years has shifted toward the evaluation of plant products as radioprotectors. Critical characteristics that may lead to the election of plants or phytochemicals for radioprotective researches include immunemodulatory, anti-inflammatory, antioxidant, antimicrobial, free radical scavenging, and anti-stress properties. The doses of plant and phytochemical preparations that were effective in radioprotection was significantly lower than the toxic dose and this is one of the major advantages of these preparations compared to synthetic compounds. Plants and phytochemicals were observed to diminish deleterious effects of IR when administered before irradiation.,,,,,Tinospora cordifolia (Family: Menispermaceae) finds a special mention for its use in tribal or folk medicine in different parts of the country.T. cordifolia root extract was administrated orally half an hour before a 2.5 Gy dose of gamma irradiation and was continued for 5 days consecutively at a dose of 75 mg/kg. This protocol effectively prevented radiation-induced alterations in body weight, tissue weight, weight index, tubular diameters, and anti-oxidative parameter viz., lipid peroxidation, glutathione (GSH), and catalase (CAT) activity in testes of mice.Acorus calamus L. (Family: Araceae), commonly known as sweet flag, is an important plant used in the ancient system of medicine. Sandeep and Nair  showed oral administration of A. calamus extract (ACE) to mice at a dose of 250 mg/kg 1 h before 2, 6, and 10 Gy gamma irradiation significantly increased the activities of major enzymes of the antioxidant defense system especially superoxide dismutase (SOD), CAT, GSH peroxidase (GPx), and levels of reduced GSH and malondialdehyde (MDA) and DNA strand breaks. It was also reported that ACE increased up to 5% survival rate in acute lethal dose of 10 Gy whole body γ-irradiation. Sandeep and Nair  in another study demonstrated that presence of ACE during irradiation prevented peroxidation of membrane lipids in mouse liver homogenate. It helped to reduce the disappearance of the covalently closed circular form of plasmid DNA following exposure to gamma irradiation. In addition, ACE effectively protected DNA from radiation-induced strand breaks and enhanced the DNA repair process. According to several phytochemical reports, salvianolic acid A (SAA) D (+)-(3, 4 dihydroxyphenyl) lactic acid is the principal effective, water-soluble constituent of Salvia miltiorrhiza Bunge (Family: Labiatae). Administration of SAA 1 h before 4 Gy gamma irradiation significantly reduced MN, comet assay parameters, γ-H2AX foci, thiobarbituric acid reactive substances level, and intracellular ROS in irradiated human normal intestinal epithelial cells (HIECs). It also significantly increased GSH and SOD levels and reduced MDA level in irradiated HIEC. SAA affected on repair of DNA damage with prompt and temporary increase in the expression of γ-H2AX at irradiated HIEC. SAA markedly increased expression of the pro-apoptotic proteins p53 and Bax and decreased the anti-apoptotic protein Bcl-2 in compared with the nonirradiated HIEC. Popov et al. demonstrated that haberlea rhodopensis extract injection (IM) to male rabbits, at a dose of 0.24 g/kg 2 h before 2 Gy gamma irradiation decreased the MDA level and increased SOD and CAT activity. Withania somnifera (L.) Dunal (ashwagandha, Indian ginseng, WS) is a perennial plant belonging to the order Solanaceae, is widely used in Ayurvedic medicine. When adult male rats received WS at a dose of 100 mg/kg for 7 consecutive days before exposure to 6 Gy of γ-irradiation, significantly reduced in serum hepatic enzymes, hepatic NO (x), MDA levels, DNA damage and significantly increased in SOD, GPx activities, and GSH content.
Further researches are needed to identify the herbal compounds responsible for radioprotective efficacy. Although there have been many plants evaluated for their ability to reduce radiation-induced damages in animals, their inadequate document at present to patronage their potential use in patients during RT.
| > Plants and Phytochemicals Against Radio-Genotoxicity in Human Peripheral Blood Lymphocyte|| |
Several studies have revealed that lymphocyte counts remain depressed years after the RT course.,,,, Hence, the reduction in DNA damage induced by IR in HPBL can lead to lymphocytopenia reduction., In the last 10 years, a significant increase seen in the use of plants and phytochemicals against IR-induced DNA damage in HPBL. These plants and phytochemicals decrease DNA damage by various mechanisms such as free radicals scavenging, reduced lipid peroxidation, increase of endogenous antioxidant defense, and enhanced DNA repair.,,, Plants and phytochemicals were evaluated against IR-induced DNA damage in HPBL with two methods. In the first method, plant or phytochemical administered orally in single nontoxic dose to healthy human volunteers and blood samples were collected in heparinized tubes before (−10 min) and 1, 2, and 3 h after the ingestion. At each of the collection times, for each volunteer, aliquots of heparinized whole blood were divided into two tubes of 1 ml. One tube was the control sample and another tube was irradiated at 37°C with X- or γ-rays., In the second method, blood samples or lymphocytes isolated from healthy human blood were incubated with plant or phytochemical for a ½–2 h. After incubation, blood samples or lymphocytes were irradiated at 37°C with X- or γ-rays.,,,
Davari et al. showed drink a decoction 4 g green tea in 280 ml boiling water for 5 constitutive days by healthy human volunteers and exposure of blood samples collected from volunteers to 2 Gy of gamma irradiation, resulted in a significant reduction of MN in compared with irradiated lymphocytes collected prior to drink. Pretreatment of human culture lymphocytes with ferulic acid, at doses of 1, 5, and 10 µg/ml 30 min before 1, 2, and 4 Gy gamma irradiation, statistically significant reduced MN and DC frequencies. Prasad et al. have reported sesamol (1, 5, and 10 µg/ml) treatment 30 min before 1, 2, and 4 Gy gamma irradiation significantly decreased MN and DC frequencies in irradiated HPBL. Mangifera indica (common name, mango) is a plant widely used in traditional medicine in different regions of the world. It is rich in polyphenols, where mangiferin is the main component. Treatment of human lymphocytes with M. indica L. (mango) stem bark aqueous extract (25 and 50 µg/ml) and mangiferin (5–25 µg/ml) 1 h before exposure to 5 Gy of γ-irradiation, resulted in reduced DNA damage (tail moment). Curcumin has radioprotective effects on normal cells, and it enhances radiation toxicity on tumor cells. The radioprotective activity of curcumin might not be due to single mechanism but to several mechanisms., The role of various concentration of curcumin was studied on the radiation-induced genotoxicity in HPBL. Treatment of HPBL with different doses (1, 5, and 10 µg/ml) of curcumin before exposure to 1, 2, and 4 Gy of gamma irradiation significantly reduced in frequency of MN and DC. In another study, Sebastia et al. showed that treatment of human lymphocytes with curcumin, at doses of 5, 50, and 500 μg/ml before 2 Gy gamma irradiation significantly decreased the frequency of DC, rings, acentrics, chromatid breaks, and gaps in irradiated lymphocytes. Moreover, maximum damage protection was reported at the concentration of 5 µg/ml. Al Suhaibani  have reported curcumin (5.0 μg/ml) treatment 30 min prior to 1 and 2 Gy of gamma irradiation significantly decreased SCE in irradiated HPBL. [Table 1] summarizes some of the plants and phytochemicals that act as radioprotector against radio-genotoxicity in HPBL.
|Table 1: Preventive effects of some plants and phytochemicals against radio-genotoxicity in human lymphocytes|
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| > Conclusions and Future Directions|| |
Nowadays, several efforts are being made to reduce RT side effects. One of such tries is to apply the total radiation dose in fractions in order to preserve healthy tissues. Moreover, searches for new treatment methods to prevent radiation consequences are continuing, as well. Some of these researches are based on prevention from oxidative damage, as the major factor responsible for radiation-induced damage. Plants and phytochemicals as radioprotector were observed to diminish IR-induced DNA damage in HPBL at doses of 1–5 Gy.,,,,,,,,,,,,,,,,, Their effects are concentration-dependent and each of them presents an optimum radioprotective dose. Although, plants and phytochemicals mentioned in this review protect against IR-induced DNA damage in HPBL, clinical trials have not yet been undertaken with most of them. Two methods are suggested for preclinical plants and phytochemicals development as radioprotector. In the first method, comprehensive toxicological and pharmacological testing is performed to address the regulatory requirement for data on absorption, distribution, metabolism, excretion, and toxicity profiles before proceeding to the clinical investigation. In the second method, the radioprotective and radiosensitive effects are determined using both in vitro and in vivo testing in both normal tissues and tumors. If radiosensitive for tumor or absence of tumor protection and sufficient normal tissue protection is found, then the mechanism of action should be identified.
Finally, among plants and phytochemicals mentioned in this review, curcumin can be considered as a candidate for future studies in reduction of cancer patients' lymphocytopenia undergoing radiotherapy, because of its remarkable properties such as radioprotective for normal cells, radiosensitive for tumor cells, readily available, inexpensive, orally administered for human, does not have toxic implications in therapeutic dose range, can act through multiple mechanisms, easy handling and storage.
Financial support and sponsorship
Tehran University of Medical Sciences and Health Services grant number 28173.
Conflicts of interest
There are no conflicts of interest.
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