Biology of radiation-induced mandibular necrosis

doi 10.15171/jrb.2018.02

Open Access

Review Article Journal of Radiobiology 2018;5(1):e02

http://www.jradiobiol.com

Biology of radiation-induced mandibular necrosis and the therapeutical perspectives for melatonin Coram Guevara1*, Luis Herrera2, Ricardo Cárdenas3, Freddy Mestre4, Heberto Suarez-Roca3,5 Abstract Radiation therapy is one of the most widely used therapeutic alternatives in the treatment of different types of orofacial cancer. Some anatomical areas in the oral cavity, including jaw bones and salivary glands, are exposed to high doses of radiation, resulting in adverse radiation-induced reactions. One of the most severe radiation-induced reactions is osteoradionecrosis (ORN), which is associated with high morbidity and a significant decrease in the patient’s quality of life. Thus, preventive and therapeutic strategies need to be implemented as to reduce its occurrence. Melatonin, a hormone produced by the pineal gland has anti-tumor, -apoptotic, -oxidant, and anti-inflammatory properties, and has been shown to improve radiation-induced lesions in several organs. Melatonin, when administered preventively, reduces the overproduction of free radicals in peripheral blood cells and apoptosis of normal cells. It also leads to over-expression of pro-inflammatory (DAMPs and TNF) and tolerogenic (TGF-β) mediators that occurs following radiation, thereby modulating the oxidative, necrotic, and fibrotic changes of ORN. Melatonin might be an effective drug for the preventive treatment of ORN. Keywords: Radiotherapy, Ionizing radiation, Osteoradionecrosis, Melatonin

Introduction The effect of x-rays on the human being is the result of interactions that occur at the atomic level (1). These interactions lead to ionization and/or excitation of the orbital electrons, causing the release of energy that, is then deposited in the tissue environment. Some cell groups are more sensitive than others to the ionizing radiation (radiosensitive cells), responding more quickly and at lower doses. For example, reproductive cells are more radiosensitive than nerve cells, and cells with high metabolic rate are more radiosensitive compared to those with lower metabolic rate (2,3). In this sense, ionizing radiation exerts two effects on the tissue; (a) direct effects, in which it acts on the molecules of sensitive cells, and (b) indirect one, where highly reactive free radicals, such as reactive oxygen species (ROS) hydroxyl radical (OH) and hydrogen ions (H), are generated by the radiation (4). These radicals react immediately with neighboring biomolecules. It is estimated that, approximately 60% and 70% of the tissue damage generated by ionizing radiation is caused by OH radicals, which interact with the cell nucleus and the cytoplasm, and as a result, affect the genetic material, organelles, and cellular metabolic processes (5). The main

markers of oxidative damage in cells are the products of lipid peroxidation, products of hydroxylation of DNA, and proteins (6). The deleterious effect of radiation on biological tissues is extremely useful in the treatment of head and neck cancer, the so-called radiotherapy as one of the most used therapeutic alternatives (7). Despite the undoubted clinical utility of radiotherapy in orofacial oncology, and regardless of having the advantage of preserving tissue structure, it causes severe adverse reactions in the oral cavity, being one of the most important cause of osteoradionecrosis (ORN) (8,9). One of the reasons for the high incidence of adverse effects is attributed to the high doses of radiation to which large anatomical areas of the patient are exposed, such as the oral cavity, maxilla, mandible, and salivary glands (10). Radiation-induced inflammation Radiation can cause cell death by various routes, such as necrosis, mitotic catastrophe, apoptosis, autophagy and senescence, and triggering the production of cytokines that can stimulate the activation of various signaling pathways in normal tissue (11). For example, apoptotic cells induce the secretion of tolerogenic cytokines by

Received: 15 January 2018, Accepted: 3 March 2018, Published online: 30 March 2018 Department of Oral Biology, Institute of Research, Faculty of Dentistry, University of Zulia, Venezuela. 2Department of Clinic and Pathology, Institute of Research, Faculty of Dentistry, University of Zulia, Venezuela. 3Section of Neuropharmacology and Neuroscience, Institute of Clinical Research (Dr. Américo Negrette), Faculty of Medicine, University of Zulia, Venezuela. 4Radiotherapy and Nuclear Medicine Service, University Hospital of Maracaibo, Venezuela. 5Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27705, USA. *Corresponding Author: Dr. Guevara S. Coram, Department of Oral Biology, Institute of Research, Faculty of Dentistry, University of Zulia, Venezuela. Phone: 00584146305291, Email: [email protected] 1

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Implication for health policy/practice/research/ medical education

Radiation-induced osteoradionecrosis (ORN) in patients undergoing head and neck radiotherapy is considered as one of the most serious complications. It occurs in approximately 20% of patients undergoing local irradiation. In this study, biology of radiation-induced mandibular necrosis and the therapeutical perspectives for melatonin were are reviewed.

macrophages, such as interleukin 10 (IL-10), platelet activating factor, transforming growth factor β (TGF-β), and prostaglandin E2 (PGE2), which exert a suppressive effect of the inflammatory response. On the other hand, the expression of molecular patterns associated with damage (DAMPs) such as the high-mobility group box 1 (HMGB1) and the oxidized DNA product of radiationinduced cell death stimulates the synthesis and secretion of proinflammatory cytokines, such as IL- 1, IL-2, IL-6, tumor necrosis factor (TNF), and interferon gamma (INF-γ) (12). Unlike tolerogenic mediators, all of these mediators have an immunogenic effect and stimulate the inflammatory response. In this sense, the inflammatory response and damage of healthy tissue induced by radiation is carried out by transcription factors such as NF-κβ, protein-kinases (e.g., MAPK), cytokines (IL-1β, IL-4, IL-5, IL-6, IL-10, IL12, IL-18, IL-33, and IFN-γ, TNF-α) and growth factors (TGF-β, bFGF, IGF-1 and PDGF) (13). This response starts with the expression of the DAMPs, which is detected by recognition pattern receptors (PRRs), such as toll-like receptors (TLRs). This, in turn, causes the activation of NF-κβ in various cells, mainly dendritic cells, neutrophils, and macrophages, which activates the signaling pathways for the synthesis of cytokines, and along with TGF-β and IGF-1, stimulates the production of prostaglandins, ROS, and NOS. The upregulation of these factors, after the exposure of high doses of radiation results in a remodeling of the extracellular matrix (ECM) that eventually can affect the tissues and produce pain, atrophy, vascular damage and fibrosis (14). Adverse reactions to radiotherapy depend mainly on the volume and irradiated surface, total dose, fractionation of the treatment (15,16). From the chronological point of view and the fractionation of the treatment, these adverse effects can be divided into two groups: (a) acute effects that are observed during or immediately after treatment, which usually represent an aggravation of pre-existing symptoms. This can be observed from few weeks to up to 2-3 months after radiotherapy is completed; (b) late effects that occur between 3 months to 12 years post-treatment (17,18). The difference between acute and delayed reactions is that, acute reactions appear during treatment and, in general, are reversible while late complications are generally irreversible, leading to permanent disability and decrease in patients’ quality of life (19). 2

Journal of Radiobiology, Vol. 5, No. 1, March 2018

Pathophysiology of osteoradionecrosis Complications that may arise after radiotherapy in patients with head and neck cancer are mainly include decreased quality of masticatory function, dysgeusia, and ORN (20). ORN is considered as the most serious complication (16), occurring in approximately 20% of patients undergoing local irradiation (21). Marx et al (22) has defined ORN as a metabolic and hemostatic deficiency resulting from tissue damage induced by radiation. ORN is characterized by the following sequence: irradiation, hypoxia, hypovascularization, and tissue hypocellularity (23). Irradiation affects the vascular endothelium, causing hyalinization of blood vessels and thrombosis (24). The periosteum becomes fibrous, the osteocytes and osteoclasts suffer necrosis, and subsequent fibrosis of the medullary spaces occurs (23,25). The ability to replace collagen and normal bone cells in irradiated tissues deteriorates extremely, even disappearing completely (23). In the beginning of the 2000s, the theory of radiationinduced fibroatrophy was proposed as the main mechanism of tissue injury in ORN (26). This theory suggests that the main event in the pathophysiology of ORN involves the activation and deregulation of fibroblast activity and the formation of atrophic tissue in previously irradiated areas (Figure 1). An in vivo fibroatrophy study has suggested that TGF-β, through the Smad proteins, plays a fundamental role in the process, since fibrosis is triggered, intensified, and maintained by the participation of the TGF-β1 subunit (27). In vitro studies have also revealed that, this pro-inflammatory cytokine can induce premature expansion and differentiation of a group of pre-fibroblast cells (26-28). During the prefibrotic phase, TGF-β1 secreted by platelets initiates a cascade of events that includes activation and

Figure 1. Pathophysiology of the development of osteoradionecrosis and possible action of melatonin.

Biology of radiation-induced mandibular necrosis

production of macrophages and release of mitogenic factors from fibroblasts (26). During the constitutive and chronic phases, peripheral TGF-β1 produced by myofibroblasts, promotes the initiation and maintenance of the fibrotic process (27). In this setting, overexpression of other inflammatory cytokines and growth factors such as thrombin, IL-1, IL-4, IL-6, TNFα, platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and connective tissue growth factor (CTGF) triggers the proliferation of smooth muscle tissue and the production of collagen from fibroblasts, leading to the fibrotic process (29). The ORN is usually observed after irradiation at a dose of above 40 Gy (30). These high doses of radiation induce lesions in the vessels due to fibrosis and hyalinization of their wall. The substitution of the normal structure of the vessel wall by fibrosis and unstructured hyaline tissue leads to a functional impairment of the local microcirculation, the vascular lumen narrows and causes ischemic necrosis of the tissue irrigated by the altered vessels (21). On the other hand, in the extracellular space, ROS induces stromal degradation, leukocyte activity (chemotaxis and phagocytosis), and fibroblast activation (31). Within the cell, adaptive responses to oxidative stress are produced through gene activation and protein synthesis, triggering a cascade of events that include DNA repair, cell cycle arrest, and secretion of growth factors, such as TNF -α, plateletderived growth factor (PDGF) and Il-1 (27). However, in vivo studies suggest that the presence of TGF-β1, other pro-inflammatory cytokines, and ROS may be molecular markers of ORN instead of predisposing factors (26,27). In this sense, it has been proposed that the best approach to cope with ORN is the prevention of severe complications associated with radiation therapy in the head and neck by using antioxidants during the peri-irradiation period. One of these antioxidants is melatonin (N-acetyl-5-methoxytryptamine), a hormone produced by the pineal gland in animals. Its main function was thought to be the regulation of sleep and wakefulness, but then it was determined to be a first-line defense molecule against oxidative stress, with remarkable anti-inflammatory properties and possible radioprotective effects (32). Melatonin as a therapeutic alternative for ORN Melatonin is an endogenous compound synthesized by various tissues, including the pineal gland in the human brain (33). Once melatonin is synthesized in the pineal gland, it reaches the cerebrospinal fluid (34-36), and subsequently, since it easily crosses the blood-brain barrier, it quickly accesses the bloodstream (37,38) and other bodily fluids (39), such as bile (40), saliva (41,42), follicular ovarian fluid (43) and semen (44). Melatonin is also synthesized in extra-cellular organs and tissues, including skin, retina and lens, the gastrointestinal tract, cells of the immune and hematopoietic systems, endocrine glands and some reproductive organs (45).

A wide variety of physiological functions have been described for melatonin (46). Melatonin can bind the cytosolic receptor MT3, which is quinone reductase 2 involved in detoxification and protective enzymatic regulation against toxic substances. It modulates immune activity by regulating the expression of antioxidant enzymes by binding orphan nuclear receptors ROR and RZR. Melatonin also exerts effects at the level of the cell surface membrane MT1 and MT2 receptors, which are related with its classical role in the modulation of circadian rhythms, participating in the seasonal variations of reproductive physiology, retinal physiology, regulation of affective and superior cognitive neurobiology, and also other functions as bone growth and regulation of blood pressure. Melatonin is also characterized by antioxidant properties that eliminate free radicals either directly (a property independent of the melatonin binding to its receptors), or indirectly, through stimulating effects on the activities of antioxidant enzymes (46-48), such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione reductase (GR), and catalase (CAT) (49,50). It has been shown that, melatonin directly neutralizes OH radicals, H2O2 and singlet oxygen, and inhibits lipid peroxidation while increasing intracellular levels of glutathione by stimulating the synthesis of the speed-limiting enzyme, γ-glutamylcysteine synthase, which inhibits the nitric oxide and lipoxygenase synthase pro-oxidative enzymes (49). There is evidences that support the stabilizing role of melatonin in microsomal membranes, potentially contributing to resist oxidative damage (51). It has also been observed that melatonin increases the efficiency of the electron transport chain, decreasing the leakage of electrons, thus reducing the generation of free radicals (52). Several studies have demonstrated that, melatonin improves radiation-induced injury in several organs, including spleen (53,54), liver (55,56), lung, colon, spinal cord (57,58), brain (59), femur (60), and salivary glands (61). In this regard, Koc et al (62) reported that melatonin, administered preemptively at a dose of 5 mg/kg, removes free radicals from peripheral blood cells in rats exposed to 5 Gy gamma radiation. It has been shown that, melatonin can have a radioprotective effect preventing cell death by apoptosis. Several in vitro and in vivo studies have provided evidence that melatonin can decrease radiationinduced apoptosis in neurons (63), retina cells (64) and bone marrow cells in rats (65), as well as in mouse thymocytes (66). Similarly, melatonin could modulate the process of apoptosis in the small intestine of mice exposed to gamma radiation at dose of 2.5 Gy (67). Recently, it has been suggested that melatonin plays a role in the reduction of radiation-induced apoptosis in rat cervical spinal cord, by inducing the expression of Bcl-2 family genes (which promote cell survival) and a significant decrease in the expression of the Bax gene (68). Finally, melatonin could Journal of Radiobiology, Vol. 5, No. 1, March 2018

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exert additional antiapoptotic effects by blocking the activity of caspase-3 that is necessary for the execution of apoptosis (69). Similarly, melatonin could modulate radiation-induced inflammation (70). It has been shown that melatonin reduces the activation of NF-κβ through the increase of Iκβ (71), as well as the signaling cascade mediated by TLR-4, MyD88, and NF-κβ. The inhibition of NFκβ by melatonin can also reduce the overproduction of leukocytes, adhesion molecules as well as the recruitment of inflammatory cells to the site of injury (72,73). As mentioned above, an immunological response is triggered in the presence of ionizing radiation and it involves the production and release of several mainly proinflammatory cytokines. In this regard, melatonin can exert an antiinflammatory effect by reducing overexpression of proinflammatory cytokines such as TNF-α, IL-1β, and IFN-γ, as well as promoting the Th2-type immune response pattern (74,75). Melatonin can also inhibit the release of TNF-α and IL-8 secreted by neutrophils, which play a leading role in the process of chronic inflammation (76). The administration of melatonin before lung irradiation can reduce the overexpression of TGF-β TNF-α and IL-6 (77). TGF-β has a suppressive effect on the expression of SOD and catalase genes; therefore, a decrease in TGF-β after exposure to ionizing radiation can reduce the effects of oxidative damage (78). As a result, decrease in the expression of the TGF-β gene is an important route for the induction of antioxidant enzymes and the reduction of oxidative damage (79). On the other hand, TGF-β has been shown to play a leading role in the fibrotic process of ORN

(Figure 2), so that melatonin can affect the development of ORN directly by reducing free radicals and oxidative processes or indirectly by inhibiting TGF–β, which will induce the expression of antioxidant enzymes and inhibit ORN-inducing fibrotic process. All of the above evidence supports the therapeutical potential of melatonin as a protector of the adverse injuries induced by radiation. In addition to its antioxidant properties and antiapoptotic effects in normal cells, it has recently been demonstrated that melatonin exerts an antitumor effect, promoting the apoptosis of tumor cells and even preventing tumor angiogenesis (the main mechanism responsible for neoplastic growth and dissemination) (80), stopping the cell cycle, regulating the expression of p53 and Bax upon discharge, and decreasing the expression of Bcl2 (81). Interestingly, in a study of Ehrlich ascitic tumor (EAC) implanted in female mice, it was observed that oral administration of melatonin reduced the viability and volume of neoplastic cells, delayed the progression of the cell cycle, and decreased the DNA content in the cellular interior. Moreover, depressed cell viability indicates that melatonin could be inducing apoptosis in EAC cells (82). Thus, melatonin could be of benefit not only to ameliorate, or even prevent, ORN but also to complement the treatment of the patient’s neoplastic process. Conclusion Radiation-induced ORN represents the most important complication for patients with head and neck cancer who received radiotherapy as the first therapeutic tool. Current knowledge about the pathogenesis of ORN supports the implementation of preventive strategies in the

Figure 2. Inflammation, fibrosis and radiation-induced oxidative damage. Mechanisms of action of melatonin on the effects of radiation on healthy tissue. ROS: reactive oxygen species. MLT: melatonin. PNM: polymorphonuclear. Mφ: macrophages. MEC: extracellular matrix.

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management of this complication. Among these strategies, melatonin emerges as a promising choice for ORN due to its antioxidant properties capable of eliminating the free radicals that are produced in the irradiated tissue as well as its anti-tumor, -apoptotic, -fibrotic, and antiinflammatory effects. Thus, clinical trials should be developed to evaluate the efficacy of melatonin as part of the pharmacological approaches for patients at risk for ORN. Authors’ contribution All the authors contributed equally to the execution and elaboration of the present manuscript. Conflict of interests The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper. Ethical considerations Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors. Also, this article does not contain any studies with human subjects. Funding/Support None declared.

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Please cite this paper as: Guevara C, Herrera L, Cárdenas R, Mestre F, Suarez-Roca H. Biology of radiation-induced mandibular necrosis and the therapeutical perspectives for melatonin. J Radiobiol. 2018;5(1):e02. doi: 10.15171/ jrb.2018.02. Copyright © 2018 The Author(s); Published by Nickan Research Institute. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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