Beneficial effects of natural products on cells during ionizing radiation.

DOI 10.1515/reveh-2014-0037 Rev Environ Health 2014; 29(4): 341–353

Review Seyed Jalal Hosseinimehr*

Beneficial effects of natural products on cells during ionizing radiation Abstract: Natural products like vegetables, fruits, and herbs are widely consumed by humans on a daily basis. These natural products have many biologic and pharmacologic properties. Ionizing radiation (IR) can interact with macromolecules like DNA, which induces serious side effects on cells and tissues. Natural products can directly scavenge free radicals produced by IR, and they can also activate or inhibit enzymes or proteins involved in the oxidative stress. Several natural products have dual biologic effects on normal and cancer cells during radiation and might be of interest for use in patients during radiotherapy. In this review, the effects of natural products on genotoxicity and cell death induced by IR were reviewed and some potentiated compounds were discussed. Keywords: ionizing radiation; natural product; radioprotective; radiosensitive. *Corresponding author: Seyed Jalal Hosseinimehr, Department of Radiopharmacy, Faculty of Pharmacy, Traditional and Complementary Medicine Research Center, Mazandaran University of Medical Sciences, Sari 48175-861, Iran, Phone/Fax: +98-151-3543084, E-mail: [email protected]; [email protected]

Introduction Ionizing radiations (IRs) are types of particles or photon rays (like γ-ray, X-ray, α and β particles) that produce ionization when passed through matter. IRs interact directly or indirectly with biologic materials in cells. IR produces reactive oxygen species (ROS) and other toxic substances that interact with critical macromolecules like DNA and cause serious cellular damage. The concentration of ROS is balanced between production of ROS during oxidative stress and the rate of elimination by endogenous antioxidant systems. The main reason for cell death is IR-induced DNA lesions (1, 2). Cell toxicity is used for killing tumor cells in radiotherapy; however, it may induce side effects on normal cells (3, 4). Natural products like vegetables, herbs, and fruits are widely consumed by humans on a daily basis. These

natural products contain active ingredients that have biologic and pharmacologic properties, and they are used in many diseases like cancer, inflammation, and diabetes. Substances originating from natural sources are interesting subjects in the ongoing search for lead compounds that can be used as drugs by patients during radiotherapy. In this review, the effects of natural products on DNA damage and cell death induced by IR were reviewed and several potential agents were discussed.

Effects of IR on macromolecules γ-Rays and X-rays are two important photons that are widely used for treatment and diagnosis in medical practices. These photons induce side effects indirectly through the production of free radicals and ROS like hydroxyl radical (OH·) and hydrogen peroxide (H2O2) (5). Free radicals are very reactive and attach quickly to other molecules with their free electrons. If these free radicals are not neutralized rapidly by a biologic defense system or an antioxidant compound in the cells, they may cause damage to the nucleus, membrane, lipids, proteins, and other cellular organelles. Extensively, ROS is produced daily, and DNA damage occurs in each cell of body. The body is equipped with defense systems for neutralizing these toxic substances. The first line of defense from the damaging effects of ROS is antioxidants, which convert the toxic substances to less reactive species (6). However, if these oxidative and antioxidant balance changes, it may lead to DNA and cell damages. IR increases markers for oxidative stress, for example, reduction in antioxidant molecules and enzymes like glutathione, manganese, and copper-zinc superoxide dismutase (MnSOD and CuZnSOD), glutathione peroxidase (GPx). GPx is the major antioxidant enzyme responsible for H2O2 detoxification in the cytosol. SOD can generate O2·– to H2O2, which can be eliminated by GPx. When cells are exposed to IR, these endogenous enzymes destroy ROS produced by IR. Overexpression of human MnSOD and GPx protects against cell injury induced by IR. MnSOD plays a central role in protecting cells against ROS injury during

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342 Hosseinimehr: Beneficial effects of natural products on cells exposure to IR. MnSOD, CuZnSOD, and GPx are involved in cellular radioresistance (7, 8). Another mechanism involved in IR-induced cellular toxicity is the bystander effect. Cells directly exposed to IR can release signals that induce the same effects on nontargeted neighboring cells. In this cross-talk, these signals are transmitted to nonirradiated cells by intercellular gapjunction communication or released markers from outside the cell. The bystander effect causes an increase in genomic instability as shown by increased frequencies of chromosomal aberrations and micronuclei and sister chromatid exchange (9, 10). A number of cellular signals are linked to this bystander phenomenon including cyclooxygenase 2 (COX-2), mitogen-activated protein kinase (MAPK), nitric oxide, and calcium signaling pathways (11).

Radiation injury to normal tissues In general, cellular radiosensitivity is dependent on mitotic and proliferating activity and degree of differentiation. Cells that have more active proliferation and less differentiation are more sensitive to radiation. Granulocytes, platelets, and erythrocytes in the bone marrow are the cells most sensitive to IR. A number of white blood cells and platelets were reduced after exposure to low dose (∼1 Gy) of IR. Radiation sickness results when humans are exposed to large doses of IR. These doses cause syndrome and manifest soon after exposure. The severity of symptoms and illness depends on the type and dose of radiation. Acute radiation sicknesses usually happen immediately after exposure to large doses of IR in radiologic, radiotherapy, or reactor accidents. Acute hematopoietic, gastrointestinal, and central nervous system (CNS) syndrome are usually observed after exposure to a large dose of IR. The hematopoietic system is one of most radiosensitive tissues in the body. Acute wholebody exposure to radiation at doses of 2–7 Gy leads to the radiation of the bone marrow, which subsequently leads to hematopoietic syndrome. Meanwhile, gastrointestinal and CNS symptoms occur after exposure to very large doses of radiation, 6 and 20 Gy, respectively (12, 13). Exposure to small doses of radiation over a long period is known as chronic exposure, and it is associated with delayed health problems like cancer.

IRs and genotoxicity IR induces a variety of DNA breaks, including single- and double-strand breaks (SSBs and DSBs, respectively). It can

produce reactive sites on other molecules, like protein, and lead to DNA-protein cross-links. If a DNA SSB is not adequately repaired, it can cause lethal chromosomal aberrations or induction of apoptosis. These damages can result in cell death. Alternatively, a misrepaired or unrepaired DSB may result in mutations or genomic rearrangements in a surviving cell, which may result in malignant cell transformation (14, 15). Cells respond to DSBs through the activation of a cascade of signal and mediator proteins that recognize the damage, and through a series of downstream effectors, induce cell-cycle arrests. These endogenous mediators complete cellular repair by homologous or nonhomologous mechanisms or trigger cell death by apoptosis. Apoptosis and cell death triggers help cells by preventing malignancy. There are two repair systems that can repair DSBs: nonhomologous end joining and homologous recombination-mediated repair. These repair systems mediate and regulate signals and proteins that accomplish enzymatic reactions of DNA end processing, rejoining, or cell cycle regulation (16, 17).

Side effects of radiotherapy It is estimated that about half of all cancer patients will receive radiotherapy during the course of their treatment for cancer (18). Although radiation exposure is optimized to targeted tumor, normal tissues also receive some unwanted IR. Local radiotherapy doses in patients with pulmonary, esophageal, colorectal, pancreatic, or pelvic malignancies are associated with significant acute toxicities that occur during radiotherapy. Bone marrow suppression is the most important dose-limiting side effect of radiotherapy. It can lead to increased risks in developing neutropenia and hemorrhage because of reduced white blood cells and platelets. However, treatment with hematopoietic growth factors has the ability to promote the recovery of bone marrow hematopoeitic function by stimulating proliferation and differentiation of bone marrow cells (19). Radiation induces injury to the gastrointestinal tract by cell death and depletion, leading to the loss of epithelium. It causes edema and mucosal inflammation, which can lead to ulceration and sepsis. Rectal bleeding and diarrhea are observed frequently in patients under pelvic radiotherapy. It is estimated that 90% of patients develop a permanent change in their bowel habits after pelvic radiotherapy, 50% of whom have an associated reduction in their quality of life (20, 21). Patients experience


Hosseinimehr: Beneficial effects of natural products on cells 343

esophagitis (difficulty swallowing) and pneumonitis (cough, fever, lung fluid accumulation) in lung cancer radiotherapy (22). Xerostomia (oral mucositis) and salivary gland dysfunction are the most common side effects in patients under head and neck radiotherapy. They are related to acute inflammatory reactions that occur within hours of radiotherapy (23). Radiotherapy can also induce varieties of cancer in patients as secondary cancers. These cancers are associated with the late effects of IR on other normal cells. Leukemia, one of the secondary cancers, usually occurs about 5–9 years after radiotherapy. The exposure of bone marrow to radiotherapy may result in considerably higher risks as compared with treatments to chest, abdominal, and pelvic fields. There is increased leukemia risk after radiotherapy of different cancers (24–26), and this side effect is caused by DNA damage on normal cells outside the primary beam during IR therapy.

Natural products Natural products refer to natural ingredients extracted directly from plants, microbial, or animal products. Recently, natural products have drawn much attention from researchers, clinicians, and the general public because of their biologic and pharmacologic properties as anti-inflammatory, antibacterial, antioxidant, and anticancer agents (27, 28). Many drugs have been derived from natural products and are widely used for the treatment of a variety of diseases, like aspirin, digitoxin, pilocarpine, taxol, and penicillins. Natural compounds have also been selected as lead compounds in the search for new drugs (29). Many animal, clinical, and epidemiologic studies have shown that the consumption of foods rich in fruits and vegetables decreased the incidence of cancers (30– 32). Several mechanisms on how natural products prevent cancer are proposed: –– antioxidant; –– induction of cell cycle arrest; –– apoptosis or inhibition of signal transduction pathways mainly the MAPK, protein kinases C, phosphoinositide 3-kinase, and nuclear factor κB (NFκB) pathways; –– activation p53 protein (encoded by a tumor suppressor gene); –– anti-inflammatory; –– anti-hormone; –– anti-angiogenesis; –– xenobiotic metabolisms and enzyme induction.

Natural compounds like tea phenols, curcumin, resveratrol, luteolin, genistein, silymarin, anthocyanin, and lycopene have been established to have chemopreventive effects (27, 30, 33, 34).

Coadministration of natural products with IR Protective effects Radioprotective agents protect macromolecules, cells, and tissues against IR-induced toxicity. These agents are administered before or immediately before exposure to radiation. Several mechanisms are proposed for radioprotective agents: –– direct scavenging of ROS; –– hydrogen donation to reactive free radicals; –– inducing/altering the levels of endogenous enzymes for detoxifying ROS; –– anti-inflammatory action; –– immunostimulant activity; –– increasing DNA stability; –– reducing the production of ROS by inducing hypoxia; –– enhancing DNA damage repair pathway (3, 35, 36). The main mechanism of radioprotective agents is the scavenging of ROS. Because DNA damage and genomic instability are mainly induced by ROS, a compound with sufficient reactivity toward ROS can intercept the free radicals before they have an opportunity to attack critical molecules. Although other mechanisms contribute indirectly to DNA damage and instability, in this way, signaling pathways initiated by IR result in induction apoptosis and cause DNA damage. Oxidative stress signaling is known to act as a mediator of biologic responses on exposure to various physical and chemical agents. For example, tumor necrosis factor (TNF-α), as a proinflammatory cytokine, serves as a signaling mediator of radiation-induced genomic instability. IR increases intracellular free radicals, which lead to increased TNFα, which, in turn, causes chromosomal instability. TNFα-induced DNA damage was blocked by antioxidants (37). Thiol-containing synthetic compounds were the first to be tested for radioprotection. These compounds protect cells and tissues against mortality induced by IR with mainly radical scavenging effect. In the past, several compounds were assayed as radioprotectors, like immunomodulators and DNA-stabilizing molecules. However,


344 Hosseinimehr: Beneficial effects of natural products on cells thiol compounds have good radioprotective effects; side effects like hypotension, nausea, vomiting, and allergy are the main problems related to use of these compounds in patients and public during exposure to IR. Thus, the use of these agents must have limited usage due to their toxicities (3). Natural products are classes of compounds including terpenoids, polyketides, amino acids, peptides, proteins, carbohydrates, lipids, nucleic acid bases, ribonucleic acids, deoxyribonucleic acid (38), and so forth. Flavonoids (Figure 1) are a family of natural products with a polyphenolic structure that are found in plants. For example, apple contains high amounts of different types of flavonoids (39). Because of their health-related effects and unique chemical structure, these bioactive compounds are the subject of research in the search for more biologic properties and mechanisms. Extensive studies of flavonoids have shown that these compounds have radioprotective properties as well as anticancer (40) antigenotoxic (41), antibacterial (42), inflammatory (43), and antioxidant (44) activities. Natural compounds have several protective effects including scavenging free radicals like hydroxyl radicals generated by γ-rays in cells. There is a possibility that pretreatment with medicinal plants with antioxidant activity could protect biologic system against oxidative stress. Because natural products have fewer side effects, they are increasingly being used as radioprotective agents. Flavonoids and herbal plants containing these polyphenols have protective effects against genotoxicity induced by γ-irradiation. Flavonoids reduce DNA damage and genomic instability induced by ROS in vitro and in vivo (Table 1). Flavonoids have excellent antioxidant activity through different mechanisms. Flavonoids with more antioxidant activity have higher radioprotective effects (81). For in vitro assays, human or animal lymphocytes were incubated with flavonoids or herbal extract and then irradiated with IR. Genetic instability was monitored with a genotoxicity assay like micronuclei, analysis metaphase, and comet. IR causes DNA damage, O

A

C O

B OH OH

Figure 1 Chemical structure of flavonoid.

and flavonoids were observed to diminish genotoxicity in human lymphocytes. Several mechanisms involved in the protective effects of flavonoids are proposed, including antioxidant activity, elevation of endogenous antioxidant enzymes, DNA repair, anti-inflammatory, immunostimulatory, and modulation of MAPK and NF-κB signaling pathways (82–85). One of the major challenges with supplemental nutritive antioxidants during radiotherapy is the possibility of tumor protection through nonselective free radical scavenging. It is clear that the main tumor-killing effects of radiotherapy are free radicals. Antioxidants may interact with the free radicals produced by the IR and reduce the effect of the radiotherapy on tumor cells. However, amifostine, a synthetic radioprotective agent selectively taken up by normal tissue and not the tumor tissue, can selectively protect normal cells against IR-induced toxicity (3, 86). Several clinical trials were performed with supplemental antioxidants during the course of radiotherapy with the goal of reducing radiation toxicity. The results have been promising. For example, antioxidants reduced xerostomia, mucositis, pulmonary fibrosis, cystitis, and alopecia during radiotherapy of patients (86). Several comprehensive surveys of the literature on concurrent administration of antioxidants along with cytotoxic therapy have controversial conclusions. Block et al. (87) and Simone and Simone (88) both found that antioxidants were at the very least harmless when given during therapy. Simone and Simone (88) surveyed the literature on supplemental antioxidants administered with chemotherapy and radiation therapy from 1996 through 2003. They identified 280 articles on this topic, of which 50 were clinical trials involving 8521 patients. Of these patients, 5081 received over-the-counter supplements like β-carotene, vitamins A, C, E, D3, and K3, B vitamins, selenium, cysteine, and glutathione as single agents or in combination. Simone and Simone (88) concluded that antioxidants and other nutrients do not interfere with therapeutic modalities for cancer. Moss (89) reviewed studies about the interference of antioxidants with radiation therapy for cancer. This researcher focused on several clinical trials on tocopherol, melatonin, pentoxifylline, and retinol and concluded that antioxidants do not conflict with the effectiveness of radiotherapy and have a beneficial outcome. Lawenda et al. (90), after a review of the literature, concluded that there are a limited number of randomized controlled trials to support the beneficial effects of antioxidants during radiotherapy and high doses of any antioxidant should be avoided during radiation therapy. The



Phyllanthus amarus

12

Plasmid pBR322 DNA

Mice lymphocytes Human lymphocytes Ileum rat

Hepatoma cell lines (HepG2 cells)

Human lymphocytes V79 Bone marrow cells, thymocytes

Plasmid DNA Splenocytes Human lymphocytes

Human lymphocytes Human lymphocytes

Punica granatum peel extract

Quercetin

Podophyllum hexandrum

Tissue

10 11

9

Vernonia cinerea

Carnosic acid δ-Tocopherol Ascorbic acide Apigenin Green tea extract Diosmine Rutin Zataria multiflora Thymol

Sesamol Syzygium cumini Rosmarinic acid

3 4 5

6 7 8

Hesperidin Hawthorn

Herbal extract or natural origin product

1 2

No.

Electrophoresis of DNA

Comet Micronuclei 8-Hydroxy-2′ deoxyguanosine (an index of oxidative DNA damage)

Comet

Micronculei Comet Micronuclei Electrophoresis of DNA

Electrophoresis of DNA Micronculei Micronuclei

Micronculei Micronculei

Assay

Quercetin Repandusinic acid, geraniin, corilagin, phyllanthusiin

Rutin

– – –

Podophyllotoxin

Sitosterol and lupeol

Thymol, carvacol –

– Epicatechin, chlorogenic acid – – –

Chemical compositions of herbal extract

Table 1 Protective effects of some natural products against DNA damage induced by IR with proposed mechanisms.

Ellagitannins and flavonoids

Flavonoid

Flavonoid

Alkaloid liganan

Phytoesterol, triterpenoid

Phenolic Phenolic

Flavonoid Phenolic and flavonoids Phenolic – Phenolic, flavonoids

Family categories

Reduced inflammatory cytokines (TNF-α, IL-1β, and IL-6) Antioxidant

Antioxidant

Enhanced antioxidant enzymes Reduced proinflammatory cytokines like TNF-α Modulates the expression of p53 Promoted cell cycle arrest in the G1 phase Antioxidant

Antioxidant Antioxidant

Antioxidant Antioxidant Antioxidant

Antioxidant Antioxidant

Proposed mechanism

(61)

(60)

(57–59)

(56)

(53–55)

(51) (52)

(48) (49) (50)

(45, 46) (47)

References


Splenocytes of mice Human lymphocyte Mice bone marrow

Ferulic acid

Resveratrol

Genistein

Propolis

Black tea extract Tinospora cordifolia

Curcumin

Haberlea rhodopensis S. cumini

Echinacea purpurea

Alstonia scholaris bark

16

17

18

19

20

21 22

23

25

26

24

15

Mice

Human lymphocyte, mice V79 Mice

Mice bone marrow, human lymphocytes Lung rat

Human lymphocytes Hepatocytes rat

V79 lung fibroblast cells Hepatocytes rats

Human lymphocytes

Caffeic acid, chrysin, and naringin Eckol

Lymphocyte, hepatocytes rat

14

Lycopene

13

Tissue


No.

(Table 1 Continued)

Chromosome aberrations, micronuclei, apoptosis Chromosomal aberrations and micronuclei

Micronuclei

Micronuclei

micronuclei Miceonuclei

Micronuclei, comet,

Chromosomal metaphase, micronuclei Micronuclei

Micronuclei Comet

Comet

Comet

Comet Micronuceli

Micronuclei

Assay

Kaempferol, quercetin, manilamine, angustilobine

Vanillic, caffeic, dihydrocaffeic Ferulic acid, catechin, anthocyanidins –

Quercetin, caffeic acid, chrysin, naringenin Epigallocatechin, caffeine Cordifolioside A

–

–

Hydroxycinnamic acid

–

–

–

Lycopene


Phenolic, polyphenolic Phenolic compound Flavonoids, alkaloids

Phenolic, flavonoid Polyphenoilc Norditerpene furan glycosides Phenolic

Polyphenolic

Polyphenolic

Phenolic

Phenolic, flavonoid Phlorotannin (polyphenolic) Phenolic

Carotenoid

Family categories

Antioxidant, immunomodulatory Increase in GSH, decrease in lipid peroxidation

Antioxidant Immunostimulating, antioxidant activities Increased enzymes antioxidants Antioxidant

Increased enzymes antioxidants and GSH Increased enzymes antioxidants Decreased the levels of the inflammatory cytokines TNF-α and IL-1β and reduced ROS Antioxidant

Reduced ROS in SEK1JNK-AP-1 pathway Increased enzymes antioxidants and GSH

Antioxidant

Increased enzymes antioxidants and GSH

Proposed mechanism

(80)

(79)

(78)

(77)

(58, 64, 74) (75) (76)

(73)

(70–72)

(69)

(67, 68)

(65, 66)

(64)

(62, 63)

References

346 Hosseinimehr: Beneficial effects of natural products on cells



use of concurrent supplemental antioxidants with chemotherapy and/or radiation therapy is warranted. However, the results of the protective effects of antioxidants on patients during radiotherapy are promising. More comprehensive clinical trials with a reasonable number of patients are needed.

enhances their effects by increasing the toxic reactions of free radicals and inhibiting the repair of the radiationinduced lethal and sublethal damage by misregulation of signal pathways (96). Table 2 summarizes some of these natural products that act as radiosensitizers in cancer cells along with IR.

Radiosensitive effects

Resveratrol

Many natural or naturally derived compounds have shown cytotoxic effects in cancer cells, and several of these compounds have been approved for clinical practice like vinblastine, vincristine, taxol, and camptothecin (91). These anticancer drugs act through several mechanisms to kill tumors: microtubule polymerization, mitotic inhibition (92), and inhibition of DNA topoisomerase I enzyme (93). Genotoxicity is the main tumoricidal effect of anticancer agents. If anticancer products are coadministrated with IR during radiotherapy; they enhance the effectiveness of radiation therapy on cancer cells. Treating cells with radiosensitizers before irradiation probably sensitizes the cell cycle phase to IR (94, 95). Other classes of natural products have not shown any anticancer effect, but they exhibit radiosensitizing effects. The presence of these compounds during irradiation

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a stilbenoid as a phenolic compound present in several plants like red grapes. Resveratrol has antioxidant activity and protects from IR-induced genotoxicity on normal human lymphocytes (71, 72). Other studies have shown that this compound selectively inhibits cellular growth and induces DNA damage in cancer cells but not in normal human cell lines. Resveratrol causes S-phase arrest and apoptotic death in cancer cells with the induction of γH2AX foci, cleaved caspase 3, and inducible COX-2 and extracellular signal-regulated kinase 1/2 (ERK1/2) pathway (110–113). Resveratrol inhibited Bcl-xL and resulted in the sensitization of cancer cells to anticancer agents. It induced apoptosis through its ability to modulate multiple cell-signaling molecules with mechanisms like drug transporters, cell survival proteins, cell proliferative

Table 2 Radiosensitive effects of some natural products against DNA damage induced by IR with proposed mechanisms. No.


Cell line

1

Genistein

2

Resveratrol

Breast cancer cells, human cervical cancer cell lines Human non-small cell lung cancer

3

4

Curcumin

Tinospora cordifolia

5

Withaferin A

6

Propolis

DU145 prostate cancer cells Sarcoma cells Human intestinal microvascular endothelial cells Colorectal tumor Ehrlich ascites carcinoma


Family categories

–

Isoflavonoid

–

Phenol

References

(97, 98)

Inhibition of NF-κB and then promotion of G2/M arrest Accompanied by NF-κB inhibition and S-phase arrest and increase in ceramide

Inhibition of NF-κB Expression of p21 and Bax

–

Berberine, palmatine, tembertarine, tinosporin –

Isoquinoline as alkaloid

Phenolic and flavonoid

Quercetin, caffeic acid, chrysin, naringenin

Phenol

Human renal cancer cells, B16F1, melanoma HNSCC

Phytosteroid

Proposed mechanism

Depletion of glutathione and glutathione-S-transferase

Downregulated Bcl-2 protein and Akt dephosphorylation Induction of G2/M block Anti-proliferative, anti-survival, increased phosphorylation of ERK1/2, Akt1


(99, 100)

(101–103)

(104)

(105–108)

(109)

348 Hosseinimehr: Beneficial effects of natural products on cells proteins, and members of the NF-κB and STAT3 signaling pathways (114, 115). The combined treatment with resveratrol and IR decreased the number of colonies and cell viability in cancer cells over radiation treatment alone. Resveratrol enhanced radiation toxicity on several cancer cells like DU145, MCF-7, HeLa, K-562, and IM-9. Other mechanisms for radiosensitizing effects of resveratrol in cancer cells are proposed to induce cell cycle at S-phase, COX-1 inhibition, and ceramide generation (100, 116, 117). Curcumin Curcumin is the yellow pigment of turmeric, which is obtained from the roots of the plant is named Curcuma longa. Curcumin has a phenol chemical structure. Curcumin exhibited antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and anticancer activities and thus is used against various diseases including diabetes, asthma, allergies, arthritis, atherosclerosis, neurodegenerative diseases, and cancer. In addition, curcumin has radioprotective effects on normal cells, and it enhances radiation toxicity on tumor cells. These effects are mediated through the regulation of numerous biochemical cascades, including various transcription factors, growth factors, inflammatory cytokines, and protein kinases like NF-κB, protein kinase C, Bcl-2, COX-2, and MAPAK (118, 119). The anti-apoptotic Bcl-2 and survivin protein were downregulated by the curcumin treatment together with enhancement of the Bax and p53 expression and caspase 3 activation. Curcumin induces DNA damage and apoptosis in cancer cell lines that are modulated by these mentioned mechanisms (120–122). Combination therapy with curcumin and IR decreased the survival rate of cancer cells compared with radiation treatment alone. Curcumin has a radiosensitive effect with enhancement of radiation toxicity on cancer cells; this effect of curcumin was observed in several cell lines exposed to IR. Curcumin caused radiation-induced apoptosis and DNA fragmentation through apoptosis proteins like p21 and Bax (101–103). Genistein Genistein is one of the most abundant isoflavones in soy. Isoflavones belong to the group of flavonoids. Because of its similar structure to human estrogen, it is also called a phytoestrogen. It has a wide variety of biologic and pharmacologic properties including antioxidant, estrogenic, and anticancer effects. The tumor cell-killing effect of this phytoestrogen is related to

–– anti-angiogenesis (blocking formation of new blood vessels); –– inhibition of several proteins involved with primary tumor growth and apoptosis (including the cyclin class of cell cycle regulators and the Akt (Protein kinase B) family of proteins); –– inhibition of the prometastatic processes of cancer cell detachment, migration, and invasion through a variety of mechanisms, including the transforming growth factor β signaling pathway; –– enhancement of proapoptotic proteins Bax, caspase 3, and caspase 9 (123–125). Genistein enhances the antitumor efficacy of gemcitabine on osteosarcoma cell lines by downregulating NF-κB and Akt (126). Genistein has radioprotective effect on normal tissues (127, 128), and several studies reported that genistein enhanced radiosensitivity in tumor cell lines in vitro like breast cancer, human cervical cancer, human esophageal squamous cancer, hepatoma, leukemia, and prostate cancer cells. Inhibition of NF-κB, promotion of G2/M arrest, and the activation of the AKT gene are the proposed mechanisms of radiosensitivity of genistein (97, 98).

Propolis Propolis, a product of honeybees, has several biologic properties like antitumoral, cytotoxic, anti-metastatic, and anti-inflammatory effects (129). Chemical analysis of propolis showed that it is contains phenolic compounds and flavonoids like caffeic acid, chrysin, quercetin, and naringenin (74). Ethanolic extract of propolis is contains more than 84% polyphenolic compounds (130). The pharmacologic properties of these compounds have protective effects against oxidative stress. Many studies showed that propolis extracts have radioprotective effects as well. It reduced IR-induced mortality in mice. Propolis has radical scavenging properties due to its flavonoids. Administration of propolis and propolis-derived compounds has been shown to stimulate hematopoietic recovery and enhances the survival of irradiated animals (130). Propolis and the water-soluble derivate of propolis mitigate DNA damage induced by IR on normal cells (64, 74, 131). Propolis and its derived compounds are not genotoxic to non-irradiated mice (57). Propolis exerts cytotoxicity in a concentrationand time-dependent manner on head and neck squamous cell carcinoma (HNSCC) like FaDu, UT-SCC15, and UT-SCC45 cell lines during exposure to IR. Propolis caused an enhancement of radiosensitivity on HNSCC cell lines,



whereas normal fibroblasts remained unaffected. Propolis induced apoptosis and caspase 3 cleavage and increased the phosphorylation of other signal killing proteins like ERK1/2, protein kinase B/Akt1 (Akt1), and focal adhesion kinase (109).

Conclusion Radiotherapy is one of the main strategies for the treatment of different cancers in patients. ROS plays the main role of destroying cancer cells when IR passes through cells. ROS attacks critical macromolecules like DNA and causes genomic instability and cell death. Humans consume fruits and vegetables daily. These compounds have active ingredients that may have biologic effects and interact with genome during radiation therapy. Natural products may have protective or sensitive effects on cell death induced by IR. However, there are different opinions on the preventive effects of natural products on normal cells vs. tumor cells during this therapy. These compounds may protect tumor cells and reduce radiation

efficacy on tumor cells with antioxidative effects through reduction of the ROS level in tumor cells. Several clinical trials have shown that the consumption of natural products has mainly preventive effects on normal cells and beneficial effects on patients. There is a critical need to use evidence-based approaches with clinical trials and cohort studies on antioxidant usage in patients during radiotherapy. In contrast, radiosensitizers can enhance the radiation efficacy on tumor cells with minimum effects on normal cells. Natural compounds that act with preventive effects on normal cells and radiosensitive effect on tumor cells include resveratrol, curcumin, genistein, and propolis. These compounds are more interesting because they have dual beneficial effects and can be selected as leading compounds for designing new drug using these mechanisms. Conflict of interest statement: The author declared no potential conflict of interest with respect to the authorship and/or publication of this review. Received February 3, 2014; accepted February 27, 2014; previously published online April 2, 2014

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Effects of ionizing radiation on differentiation of murine bone marrow cells into mast cells.

Mutagenic effects of ionizing radiation on immature rat oocytes.

Effect of ionizing radiation on human skeletal muscle precursor cells.

Effects of Ionizing Radiation on Postharvest Fungal Pathogens.

Strong effects of ionizing radiation from Chernobyl on mutation rates.

Management of ionizing radiation injuries and illnesses, Part 3: Radiobiology and health effects of ionizing radiation.

Low dose effects of ionizing radiation on normal tissue stem cells.

Time- and dose-dependent effects of total-body ionizing radiation on muscle stem cells.

Commentary on fukushima and beneficial effects of low radiation.

Interdependence of Bad and Puma during ionizing-radiation-induced apoptosis.

The health effects of low-level ionizing radiation.

Rays Sting: The Acute Cellular Effects of Ionizing Radiation Exposure.

Sterilization by ionizing radiation.

Reducing ionizing radiation doses during cardiac interventions in pregnant women.

Ionizing radiation response of primary normal human lens epithelial cells.

Review of natural products with hepatoprotective effects.

A restatement of the natural science evidence base concerning the health effects of low-level ionizing radiation.

Effects of low doses of ionizing radiation exposures on stress-responsive gene expression in human embryonic stem cells.

The effect of ionizing radiation on the fatty acid composition of natural fats and on lipid peroxide formation.

An overview of the effects of convergent magnetic ionizing radiation on biological function.

Enhanced excision repair activity in mammalian cells after ionizing radiation.

Modelling the effects of ionizing radiation on survival of animal population: acute versus chronic exposure.

Effects of Ionizing Radiation on Physical Properties of Peripherally Inserted Central Catheter.

Beneficial Effects of UV-Radiation: Vitamin D and beyond.