Protective Role of Natural Compounds under Radiation-Induced Injury: Comparison
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In recent years, eEvidence has shown the potential therapeutic effects of different natural compounds for the prevention and treatment of radiotherapy-induced mucositis (RIOM). RIOM represents one of the most frequent side effects associated with anti-neoplastic treatments affecting patients’ quality of life and treatment response due to radiation therapy discontinuation. The innate radio-protective ability of natural products obtained from plants is in part due to the numerous antioxidants possessed as a part of their normal secondary metabolic processes. However, oxygen presence is a key point for radiation efficacy on cancer cells. The aim of this reviewHere, it is to describe the most recent evidence on radiation-induced injury and the emerging protective role of natural compounds in preventing and treating this specific damage without compromising treatment efficacy.

  • radiotherapy
  • radioprotective
  • mucositis
  • radiation-induced mucositis
  • natural compounds

1. Introduction

Even though anti-neoplastic treatment has become more effective, it continues to be associated with several short and long-term side effects [1]. Radiotherapy has variable success depending on the primary tumor [2], but the toxicity or side effects associated with its use can determine several disorders, such as up- and down-gastrointestinal (GI) mucositis, which affect the quality of life of patients and treatment response possibly leading therapy discontinuation [1]. In the GI tract, the epithelial cells have the highest rate of cell proliferation and turnover in the human body [3]; the direct and indirect biological effects of radiation therapy determine the production of reactive species and proinflammatory cytokines [4] responsible for the initiation of inflammatory processes that can affect cell proliferation and surveillance.

2. Radiation-Induced Injury

Radiation can be used for different purposes: for curative intent with the aim to eradicate the disease, for neo-adjuvant intent (i.e., before surgery, to reduce the size of the disease and facilitate radical resections), for adjuvant intent (after surgery to eliminate any residual cells and reduce the risk of loco-regional recurrence) and finally for palliative purposes (such as reduction of pain or hemostatic effect). This treatment, even more when combined with systemic therapy (chemotherapy, target therapies, immunother- apy), can cause side effects that vary depending on the irradiated site. Healthy organs close to the radiation target are defined as organs at risk (OARs). The pathogenesis of late side effects is more complex. Late side effects include radiation-induced fibrosis, atrophy and vascular damage. Thus, acute and chronic side effects caused by radiation therapy follow different pathogenic pathways. Nevertheless, the severity of acute effects may have an influence on the eventual intensity of chronic effects (so-called consequential late effect).

3. Radiation-Induced Mucositis

The pathobiology of radio-induced mucositis was described by Sonis [5]: the damage process begins at the start of radiotherapy treatment. The first phase corresponds with the onset of mucositis, caused by direct and indirect damage. Radiation can activate the transcription of factors (such as NF-κB and NRF2) that can stimulate the inflammatory response. In addition, there is a massive production of pro-inflammatory cytokines that increase tissue damage. Toxicities can seriously affect the course of cancer treatment and therefore the effectiveness of therapies. Mucositis is very frequent, enough to consider that radiation-induced oral mucositis occurs in about 80% of patients with head and neck neoplasia and in 100% of patients who undergo radiotherapy treatment with multiple daily sessions (hyper-fractionated) [6].

4. From Pathogenesis to the Clinic of Mucositis

Radiation-induced damage to organs in the upper gastrointestinal (GI) tract results from the irradiation of GI neoplasms or tumors adjacent to it (e.g., head and neck, tra- chea, bronchi, mediastinal lymph nodes). This anatomical district, given the high cellular turnover, mostly suffers acute damage. The most common side effects range from loss of appetite to inflammation of the mucosa (e.g., esophagitis, duodenitis) and even ulcer and stenosis. Mucosal inflammation of the upper GI tract is often associated with an increased risk of infection by fungal agents, such as Candida albicans. From a radiobiological point of view, the type of damage that occurs at the mucosal level is deterministic: this means that as long as some “threshold” doses are maintained, no damage occurs. There are several risk factors that may increase GI toxicity. Some factors are intrinsic to the patient: advanced age, obesity, cigarette smoking, previous surgery and chronic inflammatory bowel disease. Other factors are related to the integrated treatment (for instance, the association of radi- ation with chemotherapy or other systemic therapies).

5. Preventing Measures and Treatment Modalities

The treatment of radiation-induced GI effects depends on the symptoms, the severity of the lesions and localization. Treatment options vary from supportive and dietary measures to specific medical interventions. The prevention and treatment of oral and intestinal mucositis influence patient quality of life and clinical decisions relevant to integrated therapies. The Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) published clinical practice guidelines on basic care strategies for oral mucositis. Although no guidelines were delineated for patient education and professional oral care due to limited and conflicting evidence, positive results suggest further investigations into the potential benefit of these interventions for oral mucositis management [7]. The recommendation that patient educa- tion is an integral part of patient care is supported by two new studies evaluating patient education and quality of life in cancer patients with oral mucositis.

6. The Emerging Protective Role of Natural Compounds on Radiation Injuries due to Antioxidant Activity

Plants have their own radiation protection mechanism that permits them to grow even in the presence of radiation emitted by intense sunlight [4]. The innate radioprotective ability of natural products obtained from plants is in part due to the numerous antioxidants possessed as a part of their normal secondary metabolic processes [4]. Moreover, the natural products, when administered before irradiation, have been shown to reduce the deleterious effects of infrared radiation in cells [8] . Many researchers have focused on these natural products as promising radio-protective agents against ionizing radiations [9]. The data presented by Brown et al. (2010) shows that a diet enriched with antioxidants started 24 h after a lethal radiation exposure effectively mitigated death mediated by a sparing of bone marrow cells, perhaps due to a reduction in reactive oxygen species (ROS) in murine models [10]. The most known natural product with radio-protective effects is Propolis, also known as “bee glue”, a multi-component hard resin found in beehives. Propolis has been demonstrated to have a positive effect in the alleviation of radiotherapy-induced mucositis, probably due to its antioxidant properties [40], even if the mechanism of mu- cositis is complex and not completely understood [11].

1.1. Beta-Carotene

6.1. Beta-Carotene

Beta-carotene, obtained from vegetables and fruits colored orange, yellow and red, is the precursor of vitamin A (retinol). It shows antioxidant activity inhibiting free radical damage to DNA. The beneficial effects of β-carotene are limited, as it is difficult to disperse (being a highly hydrophobic compound) and is highly reactive and unstable to oxygen, which often results in the appearance of degradation products that exhibit pro-oxidant properties . Mills and their colleagues monitored the effect of a diet enriched with beta-carotene in the worsening of oral mucosal damage during radiation and chemotherapy synchronically. Beta-carotene has a protective role on the mucosal membrane within the radiation fields used, although the number of patients studied was small . This effect may be explained by the antioxidants’ ability to scavenge free radicals that are created by the interaction between irradiation and water molecules [12].

1.2. Lutein

6.2. Lutein

Lutein is a xanthophyll carotenoid and is one of the carotenoids most present in human serum . It is the di-hydroxyl form of α-carotene , and in plants, such as kale and spinach, it is found in dark green leaves. It is especially known to be beneficial for eye health, inhibiting lipid peroxidation with greater effectiveness than β-carotene [13]. Yong et al. examined if the translocation frequency (a biomarker of cumulative DNA damage) of pilots—which are exposed to elevated levels of cosmic radiation—could be associated with intakes of specific carotenoids. They concluded that a high combined intake of vitamins and lutein–zeaxanthin from food, or a diet high in their food sources, could be effective against DNA damage under radiation [14].

1.3. Lycopene

6.3. Lycopene

In 1876, Millardet first identified lycopene in tomatoes. Lycopene is a linear, unsaturated hydrocarbon carotenoid [15]; it represents the main red pigment of fruits such as tomatoes, pink grapefruit, apricots, blood oranges and watermelon. As a member of the carotenoids, lycopene possesses 11 conjugated double bonds. Its structure, however, is thermolabile and sensitive to oxidative processes. Due to the presence of long chromophorein, the polyene chain yields many red foods . In the presence of other tomato plant constituents, particularly phytofluene, β-carotene and phytoene, its antioxidant activity is synergistically increased. Lycopene has antioxidants and is effective against free radicals on skin cells. Moreover, it is an agent with antioxidant properties often used for radiation-related disorders. Actually, Sadic et al. demonstrated that lycopene exerts radioprotective effects on rat gastrointestinal tract organs, too, especially after a high dose of administration . Motallebnejad et al. investigated if lycopene has an antioxidant effect on the oral mucosa of irradiated rats, and they demonstrated that this natural compound reduced the severity of mucositis and is useful in order to prevent radiotherapy complications (i.e., in head and neck cancers) [16].

27. Polyphenols

Phenolic compounds have attracted great interest since the 1990s due to growing evidence of their beneficial effect on human health, including anticancer activity . The phenolic compounds represent a highly heterogeneous group of molecules whose structure is characterized by the presence of a benzene ring bonded to one or more of the hydroxyl groups. They are classified according to their structure into simple, including phenolic acids, such as derivatives of cinnamic acids and benzoic, and complex phenolics, including flavonoids, tannins, and stilbenes. Phenolic compounds represent a highly heterogeneous group of molecules whose structure is characterized by the presence of a benzene ring bonded to one or more of the hydroxyl groups. Flavonoids are the most numerous and nutritionally important category of polyphenols and include flavanols, such as catechin and procyanidin; isoflavones, anthocyanins; flavanones and flavones. These compounds generally have two aromatic rings with a phenolic hydroxyl substituent (rings A and B) attached to the carbon moiety , containing 15 carbon atoms forming a C6C3C6 structure . These compounds are extensively found in the stem or trunk but also in fruits and, as secondary metabolites, in plants [17].

2.1. Caffeic Acid

7.1. Caffeic Acid

Caffeic acid is a hydroxycinnamic acid derivative and is also known as trans-caffeate or sodium caffeate (CA, (E)-3-(3,4-dihydroxyphenyl) prop-2-enoic acid). Hydroxycinnamic acids, among simple phenolic compounds, are characterized by a cinnamic acid in which the benzene ring is hydroxylated. CA has been isolated from Ilex paraguariensis, Melissa officinalis, Baccharis genistelloides and Achyrocline satureioides. It is also present in beverages such as wine, tea, coffee and apple juice [18]. It has numerous pharmacological activities including antioxidant , antiviral and anti-inflammatory . Jin et al. have suggested that pretreatment with caffeic acid could be effective for treating radiation-induced intestinal damage thanks to radioprotective effects on X-ray irradiation-induced gut injury in murine models. After 72 h radiation exposure, a significant reduction in intestinal mucosal apoptosis and oxidative stress was observed in mice pretreated with CA [19].

2.2. Gallic Acid

7.2. Gallic Acid

Gallic acid is one of the phenolic acids; it is also called gallate (GA, 3,4,5-trihydroxybenzoic acid). It is found in all living species. Some foods show high concentrations of gallic acid, including mango (Mangifera indica) , pomegranate (Punica gran-atum) , cloves (Syzygium aromaticum) , blueberries and strawberries and grape seeds [20]. The different activities of GA have been attributed to its behavior as both an antioxidant and a pro-oxidant; in fact, GA chelates transition metal ions that cause free radical damage in the human body. Moreover, gallic acid inhibited the peroxidation of membrane lipids leading to lower mortality after γ-irradiation in rats [12].

2.3. Ferulic Acid

7.3. Ferulic Acid

Ferulic acid (FA, (E)-3-(4-hydroxy-3-methoxyphenyl) prop-2-enoic acid) is a phenolic acid present in fruits and vegetables , primarily in leaves and seeds, in free form and covalently bound to lignin and other biopolymers [21]. FA is a strong membrane antioxidant in humans and is noted for its power to be protective against cancer, colds, flu, skin aging and muscle wasting. FA has been demonstrated to be a potent antioxidant that terminates free radical chains. Das et al. has demonstrated, for the first time, the protective action of FA in preventing intestinal damage due to irradiation in animal models [22].

2.4. Chlorogenic Acid

7.4. Chlorogenic Acid

Chlorogenic acids (CGAs) are esters of trans-cinnamic acids (e.g., caffeic, ferulic and p-coumaric acids) with (−)-quinic acid. They are classified into different classes according to the nature and number of cinnamic substituents and the position of esterification in the cyclohexanic ring of quinic acid. Caffeoylquinic acid, dicaffeoylquinic acids and feruloylquinic acids are the most abundant CGAs in coffee [23]. These compounds, long known as antioxidants, also slow the release of glucose into the blood stream after a meal. Various scientific evidence shows that CGAs have anti-inflammatory, anti-mutagenic, DNA damage inhibition and antioxidation properties . It has been demonstrated that CA is able to reduce mortality in animal models after γ-irradiation exposure . Moreover, CA decreases the DNA damage induced by irradiation in lymphocytes [24].

2.5. Cinnamic Acid

7.5. Cinnamic Acid

Cinnamic acid (CIA)(E)-3-phenylprop-2-enoic acid), also known as (Z)-cinnamate or 3-phenyl-acrylate, is an organic aromatic compound containing a benzene group and a carboxylic acid forming 3-phenylprop-2-enoic acid. Cinnamic acid is found in several plants, such as Panax ginseng, and also in fruits, whole grains, vegetables, honey and cinnamon (Cinnamomum cassia) . CIA is a white-colored crystalline organic acid, lightly soluble in water and modestly soluble in many organic solvents. Studies have reported that cinnamic acid shows antioxidant, antimicrobial , anticancer , neuroprotective, anti-inflammatory and antidiabetic properties [25]. Cinnamic acid terminates radical chain reactions by donating electrons that react with radicals to form stable products [26].

2.6. Epigallocatechin Gallate

7.6. Epigallocatechin Gallate

Epigallocatechin gallate is a flavonoid found in many plants, including Vitis vinifera, [(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromen-3-yl] 3,4,5-trihydroxybenzoate). It is able to inhibit cellular oxidation and prevent cell damage due to free radicals. It is under study as a potential cancer chemo-preventive agent [27]. Zhu et al. found that ECGC significantly improved the viability of human skin cells that were irradiated with X-rays and reduced X-ray irradiation-induced apoptosis. Moreover, the same authors have demonstrated that EGCG was safe and able to determine the relief of mucositis symptoms [27].

2.7. Resveratrol

7.7. Resveratrol

Resveratrol is a non-flavonoid phenol, a phytoalexin produced naturally by plants in defense against attacks by plant pathogens such as bacteria or fungi (5-[(E)-2-(4-hydroxyphenyl)ethenyl]benzene-1,3-diol). It is present in a few plant species, such as pine, pine peanut, grape, mulberry and blueberry. This phenolic compound exists in the form of two different geometric isomers, trans- and cis-piceides, but the trans form is the more stable [28]. Resveratrol is a phytoalexin , one of the polyphenolic compounds produced by plants in response to environmental stress, such as microbial infections, UV radiation and exposure to ozone . Recently, resveratrol has been shown to act as a pleiotropic biological effector, which regulates the multistage carcinogenesis process, and it was found to exhibit multiple bioactivities, including antioxidative, anti-inflammatory, cardiovascular protective and anti-aging properties. Resveratrol was investigated for its effect on growth-inhibitory activity in some human cancer cell lines, and a pro-apoptotic effect was observed in leukemia and mammary and epidermoid cell lines . Resveratrol reduces the impact of radiation on intestinal injury by improving the morphology of the intestine, suppressing crypt cell apoptosis, maintaining regeneration of cells and ameliorating activity and expression of SOD2 as compared to the control. Resveratrol is also able to activate Sirtl and to acetylate p53 expression disrupted via irradiation . One study reported the ineffectiveness of resveratrol and its metabolite piceatannol as chemical radioprotectors as they neither prevented human lung fibroblasts from radiation-induced cell death nor shielded C3H mice against lethal total body IR [29].

2.8. Rosmarinic Acid

7.8. Rosmarinic Acid

Rosmarinic acid (RA) (CR, R)-α-[[3-(3,4-dihydroxyphenyl)-1-oxo-2 E-propenyl]oxy]-3,4-dihydroxy-enzenepropanoic acid) is present prevalently in species belonging to the family Boraginaceae. RA has been first isolated and identified by two Italian in the plant Rosmarinus officinalis from which the name is derived. It is an ester of caffeic acid and 3,4-dihydroxyphenylactic acid and has various astringent, antioxidant, anti-inflammatory, anti-mutagenic, antibacterial and antiviral properties [30]. Fernando et al. have demonstrated, in human keratinocytes, that RA is able to increase the expression and activity of several enzymes usually reduced by UVB radiation—such as superoxide dismutase and catalase. Collectively, these data indicate that RA can provide substantial cytoprotection against the adverse effects of UVB radiation by modulating cellular antioxidant systems, being a potential medical agent for ROS-induced skin diseases [31].

2.9. Quercetin

7.9. Quercetin

Quercetin (QE, 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one) is one of the main flavonoids, possessing five active groups: the dihydroxy group between the A-ring, the o-dihydroxy B-group, the C-ring C2, the C3 double bond and the 4-carbonyl. It is present in fruits and vegetables, including apples, berries, brassica vegetables, tomatoes, capers, grapes, onions, spring onions and tea as well as in many flowers, bark, seeds, nuts and leaves . It is a natural polar inhibitor of auxin transport . QE is a potent antioxidant suitable for reducing inflammation [32]. Antioxidants and several naturally occurring plant phenolic glycosides, such as sinapoyl-E-glucoside (sEg), quercetin-3-O-rhamnoside-7-O- glucoside, quercetin-3-O-rhamnoside (q3Or) and luteolin-7-O- (2-apiosyl)-glucoside (l7O2ag), are promising radioprotective agents . It has been demonstrated that Calendula officinalis extract, rich in antioxidants, especially quercetin, could be effective in decreasing the intensity of radiotherapy-induced oral mucositis (OM). Forty patients with neck and head cancers under radiotherapy or concurrent chemoradiotherapy protocols were randomly assigned to receive either 2% calendula extract mouthwash or placebo; at the end of this studyere, Calendula gel could be effective in decreasing the intensity of radiotherapy-induced OM during the treatment with an antioxidant action partly responsible for the protective effect [33].

2.10 Curcumin

7.10 Curcumin

Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a yellow polyphenolic substance also known as diferuloylmethane. Its molecular structure is similar to that of other bioactive non-volatile curcuminoids, such as dimethoxycurcumin and bisdemethoxycurcumin, which differ only in the number of methoxy groups on their aromatic rings. It is extracted from the rhizomes of Curcuma longa Linn (Zingiberaceae family) and has long been known as an Indian spice with potent health benefits [34]. Chikara et al. have shown that curcumin protects normal cells from radiation-induced injuries ; curcumin possesses anti-inflammatory effects, probably thanks to the reduction in the production of inflammatory molecules and the increase in the balance between antioxidants and oxidants. Moreover, curcumin has radioprotective properties and is able to sensitize cancer cells to irradiation too. Moreover, Patil et al. have demonstrated the efficacy and safety of a curcumin mouthwash in treating the oral mucositis of patients undergoing radio-chemotherapy compared to chlorhexidine [35].

38. Vitamins

Vitamins are essential components for maintaining a healthy state, so it is important to avoid deficiencies. Vitamins are divided according to their absorption mechanism; the fat-soluble are easily absorbed by fat and the water-soluble are not easily absorbed. The best-known water-soluble vitamins are vitamin C and vitamin B complex, both of which are found in various foods, fruit, vegetables, dairy products, peas, liver, meat, eggs and cereals. In particular, vitamin B complex is important for various processes, such as normal body growth and development, skin health, proper nerve and heart function, and red blood cell formation. Thiamine, riboflavin, nia-cine, pantothenic acid, pyrixodin, biotin, folic acid and cobalamin are all part of the vitamin B complex. Vitamin C (ascorbic acid, ascorbate) is necessary for collagen growth, wound healing, bone formation, enhancing the immune system, absorption of iron and strengthening blood vessels [36]. The number of vitamin deficiencies in the head and neck cancer (HNC) population may be numerous. The focus of research conducted by Nejatinamini et al. was vitamins A, D, E, folate and B12. They showed that patients who have diets containing low vitamin content (for example, low plasma levels of 25-OH D and/or all-trans retinol) are more likely to experience mucositis during cancer treatment. Vitamins E, A, C and B have been demonstrated to be promising gastro-intestinal radioprotectors ; in fact, gamma-Tocotrienol is a vitamin E that has been demonstrated to confer protection to radiation-induced intestinal damage in vitro. Sayed et al. assessed the impact of pentoxifylline/vitamin E on the incidence and severity of RIOM in head and neck cancer patients, and at the end of the study, pentoxifylline/vitamin E combination reduced the severity and duration of acute radiotherapy-induced oral mucositis [37].

49. Compounds of a Terpenic Nature

Compounds of a terpene nature are characterized by at least one isoprene unit. They are differentiated by molecular weight and by multiples of their constituent isoprene units: monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20), triterpenes (C30) and tetraterpenes (C40). They are responsible for the fragrance, taste and pigment of plants . Monoterpenes are the most fragrant of the whole terpene family. They come from different flowers, roots (i.e., licorice), fruits and leaves; an example is limonene, which is a monoterpene found in citrus fruits that gives the characteristic aroma or α-pinene which produces the scent of pine. Sesquiterpenes, on the other hand, are important because they are responsible both for the bitter taste, which is nothing more than a defense mechanism against herbivores from feeding on them, and also for the sweet taste or flavors that are pleasing to certain organisms in order to spread their seeds and be fertilized in different areas. Triterpenes are produced by animals, plants and fungi and are known as precursors of steroids in animal and vegetable organisms and derive from mevalonic acid; although they are less known than other terpenic compounds, studies show beneficial effects on human health [38]. Among these compounds, Rocha Caldas et al. demonstrated in vivo that 1.8-cineole (a monoterpene) has antioxidant and gastroprotective activities because it significantly reduces injuries to the mucosal in indomethacin-induced gastric ulcers . A randomized controlled clinical trial assessed the role of licorice mucoadhesive film on head and neck mucositis induced by radiotherapy. They show that licorice mucoadhesive film decreases pain and the level of radiation injuries and could be administered in OM management [39].

710. Conclusions

In this Hereviewin, an interesting synthesis of several natural products with protective properties possibly effective in the prevention of RIOM is proposed. As demonstrated, these substances are natural antioxidant compounds that, when administrated before irradiation, have been shown to reduce deleterious effects of infrared radiations in cells and cellular injury mediated by inducing the expression of genes that encode detoxifying enzymes.  Numerous in vitro studies and animal model investigations have shown that several natural products may protect against cumulative DNA damage and intestinal injuries after IR exposition, prevent radiotherapy complications (especially in the treatment of head and neck cancers) and that these substances are able to determine the relief of the mucositis symptoms.  Unfortunately, it is still not possible to determine and evaluate what would be the recommended doses (e.g., in mg/day) of natural compounds able to control and reduce mucositis symptoms due to the lack of enough evidence; however, it would be interesting to determine an evaluation of recommended doses to create nutraceutical supplements in order to alleviate radiotherapy injuries, especially mucositis.  A limitation of the current literature regarding this topic is also due to the reduced number of preclinical models of radiotherapy mucositis, which does not permit to confirm the preventive effect of natural products in this pathological condition. Further studies are needed to better understand the mechanism underlying radiation-induced mucositis and the potential benefit of natural antioxidant substances for oral mucositis prevention and management.

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