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Thioctic acid in oral submucous fibrosis (India's disease) – A better tomorrow
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Review
Thioctic acid in oral submucous fibrosis (India’s disease) – A better tomorrow G.P. Bhandarkar a,*, K.V. Shetty b, A. Kulkarni c a
Department of oral medicine and radiology, A. J. Institute of Dental Sciences, Kuntikan, Mangalore, 575004 Karnataka, India Department of Pedodontia, A. J. Institute of Dental Sciences, Mangalore, India c Department of oral medicine and radiology, A. J. Institute of Dental Sciences, Mangalore, India b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 29 September 2017 Accepted 6 December 2017
Oral submucous fibrosis (OSMF), because of its common occurrence in Indian population is known as India’s disease. Regardless of diagnostic and therapeutic developments, oral potentially malignant disorders (PMD) and cancers are disseminating at a distressing rate. There is this prerequisite for unrelenting determination to find out apt treatment options so that malignant transformation may be prevented and more so the prevailing morbidity and mortality. Considering the frequency with which oral submucous fibrosis undergoes malignant transformation with free radicals playing a major part, the role of antioxidants in general and thioctic acid also known as alpha lipoic acid (ALA) in particular need to be studied in these individuals. Previous few studies indicated the use of alpha lipoic acid in oral submucous fibrosis patients leading to improvement in signs and symptoms. So, it led us to set forth and propose probable role of thioctic acid in improving symptoms in these patients. As oral submucous fibrosis poses as a threat with its various signs and symptoms and as a potentially malignant disorder as well as considering the role of free radicals in malignant transformation, we proposed the possible mechanisms behind the commonest signs and symptoms in oral submucous fibrosis and role of alpha lipoic acid in managing these signs and symptoms.
C 2017 Elsevier Masson SAS. All rights reserved.
Keywords: Alpha lipoic acid Antioxidants Burning sensation Glutathione India’s disease Malignant transformation Mechanism of action Oral cancer Oral submucous fibrosis Restricted mouth opening
1. Introduction OSMF is ‘‘an insidious chronic disease affecting any part of the oral cavity and sometimes the pharynx. Although, occasionally preceded by and/or associated with vesicle formation, it is always associated with a juxta-epithelial inflammatory reaction followed by a fibro-elastic change of the lamina propria with epithelial atrophy leading to stiffness of the oral mucosa and causing trismus and inability to eat’’ [1]. All clinical appearances that carried a risk of cancer were termed ‘‘potentially malignant disorders’’ as it reflected their extensive anatomical dissemination and OSMF is one amongst them [2]. In India, 0.2% to 0.5% population are affected with OSMF (hence called as India’s disease) [3]. Epidemiological studies revealed that chewing arecanut remains the foremost etiological factor for OSMF [4]. As OSMF is a potentially malignant disorder and free radicals act as initiators and promoters of oral carcinogenesis, this review
embarks on to hypothesize the probable role of an antioxidant such as ALA in managing OSMF as well as preventing its malignant transformation. 2. Reactive oxygen species (ROS) Arecanut has carcinogenic and clastogenic effects and is capable of generating free radicals [5]. These are compounds with one or more unpaired electrons [6]. As most of them are oxygen derived, they are called as the reactive oxygen species which initiates lipid peroxidation [7]. Free radicals produced are devastating enough to modify the cell membranes, proteins, lipids, lipoproteins, and deoxyribonucleic acid (DNA). A phenomenon called oxidative stress is created when excess of free radicals produced are not effectively destroyed by cells thus hampering normal cell growth and beginning carcinogenesis in the cell by instigating genetic mutations and modifying normal gene transcription [8]. 3. Cellular antioxidant defense system (CADS)
* Corresponding author. E-mail addresses: [email protected] (G.P. Bhandarkar), [email protected] (K.V. Shetty), [email protected] (A. Kulkarni).
The safety of cellular components from oxidative damage is brought about by antioxidants, indispensable for conserving
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Please cite this article in press as: Bhandarkar GP, et al. Thioctic acid in oral submucous fibrosis (India’s disease) – A better tomorrow. J Stomatol Oral Maxillofac Surg (2017), https://doi.org/10.1016/j.jormas.2017.12.006
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optimum health and well-being, serving as the first line of defense against free radical injury [9]. The CADS comprises of two types:
ALA should be taken 30 minutes before or 2 hours after food because of reduced bioavailability.
non-enzymatic- vitamin A, E and C; enzymatic-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) [10].
5. OSMF – signs and symptoms
SOD present in aerobic cells is responsible for converting two toxic species: superoxide (O2 –) and hydrogen peroxide (H2O2) into water. GSH-Px, a selenocysteine-reliant enzyme plays a vital role in quenching H2O2 in cells [9]. 4. ALA (Thioctic acid) Antioxidant (B. Halliwell-1995) ‘‘Any substance that, when present at low concentrations compared with those of an oxidizable substrate, significantly delays or prevents oxidation of that substrate’’ [6]. ALA (1,2-dithiolane-3-pentanoic acid) [6] and it’s reduced form dihydrolipoic acid (DHLA) are often called the ‘‘universal antioxidant’’ and are vital cofactors for various mitochondrial bioenergetic enzymes like pyruvate dehydrogenase and ketoglutarate dehydrogenase [11]. Atherosclerosis, lung, neurodegenerative disorders and chronic inflammation involves peroxynitrite production which are quenched by DHLA [12]. 4.1. Mechanism of action 4.1.1. Metal chelation Redox-active metals like free iron, copper, manganese and zinc are chelated by ALA and DHLA as direct ROS scavengers. This prevents oxidative damage from highly reactive free radicals generated by catalyzing reactions thus making ALA a useful tool in the treatment of chronic diseases [11]. 4.1.2. ROS scavenger As ALA is both hydrophilic and lipophilic, it acts in the cytosol, lipoproteins, serum and plasma membrane. ALA scavenges oxygen singlets, hypochlorous acid and hydroxyl radicals and DHLA scavenges peroxyl and superoxide radicals leading to inhibition of free radical-mediated peroxidation of proteins without becoming involved in the process [11]. 4.1.3. Regeneration of endogenous antioxidants Free radicals are scavenged by an antioxidant: to scavenge additional ROS, it must first be reduced as it is already oxidized. Essential antioxidants including vitamin C, vitamin E and glutathione are reduced and regenerated from their oxidized forms by DHLA which is a powerful reducing agent [11]. 4.1.4. Oxidative damage repair Nicotinamide adenine dinucleotide (NADH) is made available as a source for reductive reactions by ALA. In addition, DHLA improves the action of peptide methionine sulfoxide reductase (PMSR) thereby mending oxidative damage to proteins [6]. 4.2. Dosage Orally, ALA can be given in the range of 600–1800 mg daily. IV doses are given in the range of 300–600 mg [13].
OSMF presents with various findings of which the most relevant are: 5.1. GSH depletion The mechanism underlying arecoline-induced cytotoxicity is possibly due to GSH depletion playing a key role in the pathogenesis of fibrosis. GSH depleted buccal mucosa fibroblasts in OSMF were found to be more susceptible to other reactive agents within the areca quid. Thus, areca chewers agonized from OSMF at a high risk ratio for oral cancer. Arecoline-induced cyclooxygenase (COX-2) is critically reliant on intracellular GSH concentration [14]. 5.2. Burning sensation It is the most common presenting complaint of the patient which precludes him from consuming regular food comfortably resulting in various deficiency states. Various hypotheses: coarse fibers of arecanut results in micro trauma [15] of the buccal mucosa which probably leads to erosions; 4-hydroxylproline found solely in collagen requires iron and ascorbic acid for the reaction. As OSMF is principally a collagen disorder, iron is used up resulting in decreased iron levels leading to improper vascular channel formation and attendant reduction in vascularity. Iron containing enzyme cytochrome oxidase is required for normal epithelial maturation. As a result of reduced iron levels, low levels of this enzyme causes subsequent atrophy of epithelium, leading to burning sensation and ulcerations of the oral cavity in areca chewers. Thus ingestion of regular diet may be unpleasant for the patient further leading to anemia [16]; increased fibrosis of minor salivary gland (MSG) was reported to be associated with increased burning sensation of the oral cavity [17]. In OSMF, there is decrease in the salivary secretion as a result of fibrosis and hyalinization in and around MSG resulting in reduced secretion of mucins (insulators) [18] at the tips of microplicae (oral mucosal barrier complex) of superficial cells of the oral epithelium [19]. This results in decreased salivary mucus gel (SMG) production leading to SMG barrie\r loss producing the following consequences [17]: In OSMF, normal physiologic friction results in rapid exfoliation of superficial cells of the oral epithelium owing to less protection leading to epithelial atrophy. The surface is further sensitive to burning sensation as a result of decrease in the distance of intra-epithelial nerve endings from the surface. Furthermore, burning sensation is also because of spicy food elements diffusing easily towards intra-epithelial nerve endings as a result of diminished defensive diffusion membrane (DDM) function of SMG [17]: lesional keratinocytes showed nuclear positivity for phosphorylated SMAD2, suggesting the role of transforming growth factor beta (TGF-b1) in inhibiting the epithelial growth and thereby causing pronounced epithelial atrophy in OSMF [20];
Please cite this article in press as: Bhandarkar GP, et al. Thioctic acid in oral submucous fibrosis (India’s disease) – A better tomorrow. J Stomatol Oral Maxillofac Surg (2017), https://doi.org/10.1016/j.jormas.2017.12.006
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G2/M cell cycle arrest and increased sub-G0/G1 population is a hallmark of apoptosis caused by arecoline. The impairment of vascular function through endothelial damage possibly contributed to the pathogenesis of OSMF [21]. This reflected the reduced vascularity witnessed in histological sections of OSMF as the disease advanced. This led to atrophy of the epithelium and a hypoxic environment is created predisposing to carcinogenesis [20]. the likelihood of cytotoxic and genotoxic effects of inducible nitric oxide synthase(iNOS) on adult stem cell pools of epithelium due to it’s expression and over activity in OSMF probably leads to epithelial thinning [22]; cytokeratin-18 (CK18) which is used to assess the level of cell multiplication is probably related with epithelial atrophy of OSMF [23]; the anterior region of the mouth (has most prominent connective tissue papillae) has greater density of sensory receptors than the posterior region [24]. So it is possible that burning sensation is felt more in the anterior than in the posterior area of the mouth on consuming spicy food. lastly, adding on the biochemical functions of vitamin A, it is essential to maintain a healthy epithelial tissue. Further, retinyl phosphate is essential for the formation of mucopolysaccharides, compounds of mucus secreted by the epithelial cells to maintain a moist surface [25]; previous studies have found reduced serum vitamin A levels in OSMF patients. Mucous membranes are stabilized by vitamin A as its deficiency results in loss of mucous secreting cells and epithelial atrophy leading to mucosal irritation. Reduced bioavailability of vitamin A in OSMF mirrored its increased consumption to scavenge lipid peroxidation product, malondialdehyde (MDA) which is increased in OSMF [26]. All the above factors possibly play a role in atrophy of the epithelium resulting in burning sensation on consuming spicy food in these patients. 5.3. Restricted mouth opening It is one of the most imperative presenting symptom as well as sign in the later clinical stages which hampers the patient in consuming food thus leading to cachexia and possibly death. 5.4. Aetiopathogenesis Arecanut alkaloids causes chemical injury to the buccal mucosa provoking a defensive inflammatory response. This continuous process of arecanut chewing leads to chronic inflammation [27]. In certain inflammatory diseases, prostaglandin synthesis is brought about by an enzyme, COX-2. In OSMF, epithelial cells, fibroblasts and inflammatory cells revealed strong immunostaining for COX-2. This suggests that chronic inflammation triggered by arecolineinduced cell injury is customarily followed by excessive fibrosis [14]. In response to injury, several inflammatory mediators such as prostaglandin E2 (PGE2), interleukin 6 (IL-6), tumour necrosis factor-alpha (TNF-a) and more outstandingly TGF-b are secreted by keratinocytes [20]; The regulation of inflammatory reaction as well as transcriptions of collagen and collagenase is brought by TNF-a which facilitates multiple functions [28];
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TGF-b favours collagen production by moderating three main events: triggering of procollagen genes, raising procollagen proteinases levels, lysyl oxidase (LOX) activity is up regulated [27]. in OSMF, there is striking up-regulation of avb6 integrin which triggers TGF-b1, the key modulator of tissue fibrosis. TGF-b1 causes trans-differentiation of oral fibroblasts into myofibroblasts facilitating matrix accumulation by increasing the deposition of matrix proteins mainly in the form of collagen I and decreasing the degradation of matrix proteins by upregulating the tissue inhibitor of matrix metalloproteinases (TIMP-1) gene [20]; a review described the pathogenesis of OSMF in detail with special emphasis on copper [29]. LOX is a copper-dependent enzyme, vital for the cross-linking of collagen and elastin [30]. producing insoluble collagen that is unaffected by proteolysis [27]. The copper content of arecanut is high and the up regulation of LOX [31] suggests it’s possible role in fibrogenesis [30]. ROS elicited by arecoline-induced cell injury triggers nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), c-Jun N-terminal protein kinase (JNK) and p38 mitogenactivated protein kinase (MAPK) with subsequent connective tissue growth factor (CTGF) expression in buccal mucosal fibroblasts. It is possible that the fibrotic activity in OSMF is enhanced by overexpression of CTGF and basic fibroblast growth factor (bFGF) [32] thus playing a role in the pathogenesis [20]; one study found that as histopathological grades of OSMF progressed, the levels of tissue MDA decreased which possibly reflected its consumption in cross-linking of collagen [33]; TGF-b reduces the collagen degradation by moderating two main events: TIMP-1 gene is triggered and thus impedes activated collagenases; triggering of plasminogen activator inhibitor (PAI) gene. Consequently, plasmin is not produced for active collagenase formation [27]. there is down regulation of the main human enzyme matrix metalloproteinase-1 (MMP-1) which degrades fibrillar collagen and also bone morphogenetic protein 7 (BMP7, negative modulator of fibrosis) leading to increased deposition of collagen in OSMF [20]; fibroblast phagocytosis is suppressed by arecoline leading to OSMF [34]. Weakening of the immunity ensues as a result of inhibition of T cell activity by arecanut extracts [35]. Continuous accretion of collagen with triggering of signaling pathways such as ALK5, JNK, SMAD and p38 MAPK is contributed by TNF-a, bFGF and CTGF while the chief mediator of OSMF seems to be TGF-b [20]. All the above factors seem to play a pivotal role in restricted mouth opening seen classically in higher clinical stages of OSMF.
6. Role of ALA in OSMF 6.1. Improved GSH levels Incessant antioxidant activities are executed efficiently by vitamin A and C which is mediated by the most indispensable and potent antioxidant, glutathione. Neutralization of the free
Please cite this article in press as: Bhandarkar GP, et al. Thioctic acid in oral submucous fibrosis (India’s disease) – A better tomorrow. J Stomatol Oral Maxillofac Surg (2017), https://doi.org/10.1016/j.jormas.2017.12.006
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radicals leads to consumption of antioxidants. Antioxidants become active afresh when they return to their standard electron configuration and this is brought about by reduced glutathione. Thus, the antioxidant levels in the body are upheld by GSH. Execution of various functions results in diminution of reduced glutathione [10]. Intracellular levels of glutathione is improved by ALA administration [36] and glutathione is reduced and regenerated by DHLA [11]. Thus ALA probably intercepts the conversion of lower clinical stages of OSMF into higher ones. 6.2. Resolvement of burning sensation As mentioned previously, intracellular levels of glutathione is improved by ALA administration [36] and glutathione aids vitamin A in performing it’s antioxidant activities efficiently [10]. Thus, the integrity of the epithelium is maintained reducing it’s atrophy and ensuing burning sensation. As ALA and DHLA quenches the free radicals, TGF-B1 as well as iNOS are probably not expressed. As a result perhaps there is no more inhibition of the epithelial growth(epithelial thinning) thereby reducing epithelial atrophy and ensuing burning sensation. Also, ALA possibly acts as a neuroprotective agent thus reducing burning sensation of the oral mucosa [37]. 6.3. Progress in mouth opening In a study, patients treated with ALA and intralesional injections of steroids and hyaluronidase showed reduced burning sensation of the oral mucosa and progress in mouth opening values as compared to the group treated with intralesional injections alone [38]. 6.4. Probable mechanism of action As LOX is a crucial enzyme in inducing fibrogenesis, curbing the activity of LOX by using a copper chelator may help in reducing the fibrosis by preventing cross-linking of the collagen fibers [27]. Redox-active metals like copper are chelated by ALA and its reduced form, DHLA functioning as ROS scavengers as well as copper chelators [11]. So probably there is reduction of further process of fibrosis. Improved mouth opening also appears to be due to the improved levels of glutathione whose depletion has an important role in the pathogenesis of fibrosis. Intracellularly, glutathione is the main redox buffering thiol playing an essential role in lymphocytic function and activation of T-cells [37]. Thus probably, the cell mediated immunity and phagocytic activity of the cells are improved resulting in collagen degradation. Glutathione-aided vitamin A functions efficiently in scavenging MDA leading to possible prevention of crosslinking of collagen. One study found reduced plasma levels of IL-6 protein (proinflammatory cytokine) by ALA administration resulting in subdual of the inflammatory process [39]. Proinflammatory cytokines such as TNF, triggered molecular signaling pathways leading to inflammatory response which was inhibited by ALA [11]. So, the most crucial step that is, the inflammatory process is halted by ALA making it perhaps an effective anti-inflammatory agent as well. Also as chronic inflammation is invariably followed by fibrosis, further inflammation and subsequent fibrosis may be prevented by ALA as it quenches peroxynitrite radicals. NF-kappa B, JNK and p38 MAPK pathway is probably blocked as a result of ROS scavenging by ALA and thus subsequent prevention of CTGF overexpression.
It was shown that for hypoxia-induced TGF-b1 up regulation, ROS was essential [20]. As ROS is scavenged by ALA, TGF-b1 and TIMP-1 is probably not expressed(down regulated) and MMP-1 is no longer down regulated. All these probably are the reasons for an improved mouth opening observed in the study mentioned above. 6.5. Possible prevention of carcinogenesis OSMF is one of the most common amongst PMDs, frequently heralding oral squamous cell carcinoma (OSCC) [9]. In arecanut chewers, primary oral keratinocytes may initiate inflammation of the buccal mucosa by production of PGE2, TNF-a and IL-6 leading to OSMF and contributing to the pathogenesis of cancer by marring T cell activation [40]. A study confirmed striking up regulation of hypoxia-inducible factor 1-alpha (HIF-1a) and attendant epithelial dysplasia and progression in fibrosis in OSMF samples suggesting it’s possible role in malignant transformation [41]. Migration of the keratinocytes and initiation of invasion is stimulated by arecoline-dependent avb6 up-regulation probably indicating its’s part in malignant transformation (more than 80%) [42]. Disparity between the existence of ROS and CADS creates oxidative stress which is observed in OSCC [43]. Substantial proof advocates that the inhibition of both initiation and promotion of carcinogenesis is performed by antioxidant enzymes. Progression of cancer is due to the low activities of these enzymes [44]. One study found that the serum and salivary total antioxidant capacity levels decreases as severity of OSMF increases [45]. The premalignant potential of OSMF may be allied with its reduced serum levels of GSH-Px and SOD in such patients [3]. Reduction of antioxidants and formation of oxidative stress like milieu in OSMF patients is due to the diminution in plasma GSH levels [10]. These patients are incapable of scavenging ROS [10] thus contributing to carcinogenesis as ROS and free radicals are implicated in malignant transformation [9]. 6.6. Probable mechanism of action ALA is supposed to augment the functional life span and preserve the genomic and structural integrity of mitochondria by guarding it against respiration-linked oxidative stress. NF-B pathway for which TNF is a key activator mediates inflammatory responses and regulates expression of several inflammatory mediators. NF-B also activates COX-2 and iNOS involved in inflammatory process. Molecular signaling pathways activated by proinflammatory cytokines such as TNF is inhibited by ALA by suppressing the inflammatory response which is crucial in carcinogenesis [11]. ALA helps in the inhibition and management of oxidative stress facilitated pathological disorders as enormous amounts of free radicals are quenched by it [11]. Thus, ALA may also be beneficial in OSMF which is in itself another classic example of an oxidative stress situation. Also as ALA quenches ROS and improves intracellular GSH levels which is an important antioxidant enzyme, it might play a vital role in prevention of carcinogenesis in OSMF patients. ALA is a natural antimutagene exhibiting antimutagenic and anticarcinogenic actions, exemplifying a prospective therapeutic agent for the vascular endothelium [11]. Also, as mentioned previously, ALA probably controls fibrosis in the connective tissue by acting mainly as a ROS scavenger and copper chelator leading to possible improvement in the vascula-
Please cite this article in press as: Bhandarkar GP, et al. Thioctic acid in oral submucous fibrosis (India’s disease) – A better tomorrow. J Stomatol Oral Maxillofac Surg (2017), https://doi.org/10.1016/j.jormas.2017.12.006
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ture reducing hypoxia and subsequent risk of developing epithelial dysplasia. 7. Conclusion The inference of oxidative stress in the etiology of OSMF suggests that antioxidant therapy such as ALA perhaps epitomizes a healing touch in the path of management. The role of ROS is noteworthy in both pathogenesis and malignant transformation of OSMF. Therefore, momentous therapeutic benefits are offered by antioxidants in managing the disease and preventing its malignant transformation. Intralesional injections of steroids and hyaluronidase have shown proven success in mouth opening; but as substantial pain, discomfort etc follows, ALA appears promising in the management of OSMF alone or as an adjunct thus minimizing the overall treatment time. More studies should be conducted in higher clinical stages so that ALA may be used as a first line therapy in medical management. Future directions should aim at conducting further studies to confirm the benefits of ALA in OSMF and especially its role in the prevention of malignant transformation in these patients. Meanwhile, these patients should be advised to do regular mouth opening exercises and to be cautious about the various clastogenic habits such as consumption of arecanut, tobacco in any form, alcohol and motivated to stop the habit which in itself must be the first line of management. Ethical statement We, the authors of this manuscript state that the manuscript has been read and approved by us and that the requirements for authorship have been met, and we believe that the manuscript represents honest work. I, Dr Gowri located and selected the articles, and acquired and analysed the data. Both I, Dr Gowri, Dr Kushal and Dr Arati drafted the article, prepared the manuscript and revised it. Final approval of the version to be published is given by myself Dr Gowri, Dr Kushal and Dr Arati. Role of the funding source Nil. Disclosure of interest The authors declare that they have no competing interest. References [1] Kamath VV, Satelur K, Komali Y. Biochemical markers in oral submucous fibrosis: a review and update. Dent Res J 2013;10:576–84. [2] Warnakulasuriya S, Johnson NW, Van der Waal I. Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med 2007;36:575–80. [3] Uikey AK, Hazarey VK, Vaidhya SM. Estimation of serum antioxidant enzymes superoxide dismutase and glutathione peroxidase in oral submucous fibrosis: a biochemical study. J Oral Maxillofac Pathol 2003;7:44–5. [4] Tilakaratne WM, Klinikowski MF, Saku T, Peters TJ, Warnakulasuriya S. Oral submucous fibrosis: review on aetiology and pathogenesis. Oral Oncol 2006;42:561–8. [5] Patel JB, Shah FD, Shukla SN, Shah PM, Patel PS. Role of nitric oxide and antioxidant enzymes in the pathogenesis of oral cancer. J Cancer Res Ther 2009;5:247–53. [6] Biewenga GP, Haenen GR, Bast A. The pharmacology of the antioxidant lipoic acid. Gen Pharmacol 1997;29:315–31. [7] Gupta S, Reddy MVR, Harinath BC. Role of oxidative stress and antioxidants in aetiopathogenesis and management of oral submucous fibrosis. Indian J Clin Biochem 2004;19:138–41. [8] Pham-Huy LA, He H, Pham-Huy C. Free radicals, antioxidants in disease and health. Int J Biomed Sci 2008;4:89–96.
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[40] Jeng JH, Wang YJ, Chiang BL, et al. Roles of keratinocyte inflammtion in oral cancer: regulating the prostaglandin E2, interleukin-6 and TNF-a production of oral epithelial cells by areca nut extract and arecoline. Carcin 2003;24:1301–15. http://dx.doi.org/10.1093/carcin/bgg 083. [41] Tilakaratne WM, Iqbal Z, Teh MT, et al. Up regulation of HIF-1a in malignant transformation of oral submucous fibrosis. J Oral Pathol Med 2008;37:372–7. [42] Moutasim KA, Jenei V, Sapienza K, et al. Betel-derived alkaloid up-regulates keratinocyte alphabeta 6 integrin expression and promotes oral submucous fibrosis. J Pathol 2011;223:366–77. http://dx.doi.org/10.1002/path.2786.
[43] Yokoe H, Nomura H, Yamano Y, et al. Alteration of extracellular superoxide dismutase expression is associated with an aggressive phenotype of oral squamous-cell carcinoma. Exp Ther Med 2010;1:585–90. http://dx.doi.org/ 10.3892/etm_00000092. [44] Gokul S, Patil VS, Jailkhani R, Hallikeri K, Kattappagari KK. Oxidant-antioxidant status in blood and tumor tissue of oral squamous cell carcinoma patients. Oral Dis 2010;16:29–33. [45] Shekhawat C, Babu S, Gopakumar R, et al. Oxidative stress in oral submucous fibrosis – a clinical and biochemical study. OHDM 2016;15:1–5 [http://www. omicsonline.com].
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Review
Thioctic acid in oral submucous fibrosis (India’s disease) – A better tomorrow G.P. Bhandarkar a,*, K.V. Shetty b, A. Kulkarni c a
Department of oral medicine and radiology, A. J. Institute of Dental Sciences, Kuntikan, Mangalore, 575004 Karnataka, India Department of Pedodontia, A. J. Institute of Dental Sciences, Mangalore, India c Department of oral medicine and radiology, A. J. Institute of Dental Sciences, Mangalore, India b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 29 September 2017 Accepted 6 December 2017
Oral submucous fibrosis (OSMF), because of its common occurrence in Indian population is known as India’s disease. Regardless of diagnostic and therapeutic developments, oral potentially malignant disorders (PMD) and cancers are disseminating at a distressing rate. There is this prerequisite for unrelenting determination to find out apt treatment options so that malignant transformation may be prevented and more so the prevailing morbidity and mortality. Considering the frequency with which oral submucous fibrosis undergoes malignant transformation with free radicals playing a major part, the role of antioxidants in general and thioctic acid also known as alpha lipoic acid (ALA) in particular need to be studied in these individuals. Previous few studies indicated the use of alpha lipoic acid in oral submucous fibrosis patients leading to improvement in signs and symptoms. So, it led us to set forth and propose probable role of thioctic acid in improving symptoms in these patients. As oral submucous fibrosis poses as a threat with its various signs and symptoms and as a potentially malignant disorder as well as considering the role of free radicals in malignant transformation, we proposed the possible mechanisms behind the commonest signs and symptoms in oral submucous fibrosis and role of alpha lipoic acid in managing these signs and symptoms.
C 2017 Elsevier Masson SAS. All rights reserved.
Keywords: Alpha lipoic acid Antioxidants Burning sensation Glutathione India’s disease Malignant transformation Mechanism of action Oral cancer Oral submucous fibrosis Restricted mouth opening
1. Introduction OSMF is ‘‘an insidious chronic disease affecting any part of the oral cavity and sometimes the pharynx. Although, occasionally preceded by and/or associated with vesicle formation, it is always associated with a juxta-epithelial inflammatory reaction followed by a fibro-elastic change of the lamina propria with epithelial atrophy leading to stiffness of the oral mucosa and causing trismus and inability to eat’’ [1]. All clinical appearances that carried a risk of cancer were termed ‘‘potentially malignant disorders’’ as it reflected their extensive anatomical dissemination and OSMF is one amongst them [2]. In India, 0.2% to 0.5% population are affected with OSMF (hence called as India’s disease) [3]. Epidemiological studies revealed that chewing arecanut remains the foremost etiological factor for OSMF [4]. As OSMF is a potentially malignant disorder and free radicals act as initiators and promoters of oral carcinogenesis, this review
embarks on to hypothesize the probable role of an antioxidant such as ALA in managing OSMF as well as preventing its malignant transformation. 2. Reactive oxygen species (ROS) Arecanut has carcinogenic and clastogenic effects and is capable of generating free radicals [5]. These are compounds with one or more unpaired electrons [6]. As most of them are oxygen derived, they are called as the reactive oxygen species which initiates lipid peroxidation [7]. Free radicals produced are devastating enough to modify the cell membranes, proteins, lipids, lipoproteins, and deoxyribonucleic acid (DNA). A phenomenon called oxidative stress is created when excess of free radicals produced are not effectively destroyed by cells thus hampering normal cell growth and beginning carcinogenesis in the cell by instigating genetic mutations and modifying normal gene transcription [8]. 3. Cellular antioxidant defense system (CADS)
* Corresponding author. E-mail addresses: [email protected] (G.P. Bhandarkar), [email protected] (K.V. Shetty), [email protected] (A. Kulkarni).
The safety of cellular components from oxidative damage is brought about by antioxidants, indispensable for conserving
https://doi.org/10.1016/j.jormas.2017.12.006 C 2017 Elsevier Masson SAS. All rights reserved. 2468-7855/
Please cite this article in press as: Bhandarkar GP, et al. Thioctic acid in oral submucous fibrosis (India’s disease) – A better tomorrow. J Stomatol Oral Maxillofac Surg (2017), https://doi.org/10.1016/j.jormas.2017.12.006
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optimum health and well-being, serving as the first line of defense against free radical injury [9]. The CADS comprises of two types:
ALA should be taken 30 minutes before or 2 hours after food because of reduced bioavailability.
non-enzymatic- vitamin A, E and C; enzymatic-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) [10].
5. OSMF – signs and symptoms
SOD present in aerobic cells is responsible for converting two toxic species: superoxide (O2 –) and hydrogen peroxide (H2O2) into water. GSH-Px, a selenocysteine-reliant enzyme plays a vital role in quenching H2O2 in cells [9]. 4. ALA (Thioctic acid) Antioxidant (B. Halliwell-1995) ‘‘Any substance that, when present at low concentrations compared with those of an oxidizable substrate, significantly delays or prevents oxidation of that substrate’’ [6]. ALA (1,2-dithiolane-3-pentanoic acid) [6] and it’s reduced form dihydrolipoic acid (DHLA) are often called the ‘‘universal antioxidant’’ and are vital cofactors for various mitochondrial bioenergetic enzymes like pyruvate dehydrogenase and ketoglutarate dehydrogenase [11]. Atherosclerosis, lung, neurodegenerative disorders and chronic inflammation involves peroxynitrite production which are quenched by DHLA [12]. 4.1. Mechanism of action 4.1.1. Metal chelation Redox-active metals like free iron, copper, manganese and zinc are chelated by ALA and DHLA as direct ROS scavengers. This prevents oxidative damage from highly reactive free radicals generated by catalyzing reactions thus making ALA a useful tool in the treatment of chronic diseases [11]. 4.1.2. ROS scavenger As ALA is both hydrophilic and lipophilic, it acts in the cytosol, lipoproteins, serum and plasma membrane. ALA scavenges oxygen singlets, hypochlorous acid and hydroxyl radicals and DHLA scavenges peroxyl and superoxide radicals leading to inhibition of free radical-mediated peroxidation of proteins without becoming involved in the process [11]. 4.1.3. Regeneration of endogenous antioxidants Free radicals are scavenged by an antioxidant: to scavenge additional ROS, it must first be reduced as it is already oxidized. Essential antioxidants including vitamin C, vitamin E and glutathione are reduced and regenerated from their oxidized forms by DHLA which is a powerful reducing agent [11]. 4.1.4. Oxidative damage repair Nicotinamide adenine dinucleotide (NADH) is made available as a source for reductive reactions by ALA. In addition, DHLA improves the action of peptide methionine sulfoxide reductase (PMSR) thereby mending oxidative damage to proteins [6]. 4.2. Dosage Orally, ALA can be given in the range of 600–1800 mg daily. IV doses are given in the range of 300–600 mg [13].
OSMF presents with various findings of which the most relevant are: 5.1. GSH depletion The mechanism underlying arecoline-induced cytotoxicity is possibly due to GSH depletion playing a key role in the pathogenesis of fibrosis. GSH depleted buccal mucosa fibroblasts in OSMF were found to be more susceptible to other reactive agents within the areca quid. Thus, areca chewers agonized from OSMF at a high risk ratio for oral cancer. Arecoline-induced cyclooxygenase (COX-2) is critically reliant on intracellular GSH concentration [14]. 5.2. Burning sensation It is the most common presenting complaint of the patient which precludes him from consuming regular food comfortably resulting in various deficiency states. Various hypotheses: coarse fibers of arecanut results in micro trauma [15] of the buccal mucosa which probably leads to erosions; 4-hydroxylproline found solely in collagen requires iron and ascorbic acid for the reaction. As OSMF is principally a collagen disorder, iron is used up resulting in decreased iron levels leading to improper vascular channel formation and attendant reduction in vascularity. Iron containing enzyme cytochrome oxidase is required for normal epithelial maturation. As a result of reduced iron levels, low levels of this enzyme causes subsequent atrophy of epithelium, leading to burning sensation and ulcerations of the oral cavity in areca chewers. Thus ingestion of regular diet may be unpleasant for the patient further leading to anemia [16]; increased fibrosis of minor salivary gland (MSG) was reported to be associated with increased burning sensation of the oral cavity [17]. In OSMF, there is decrease in the salivary secretion as a result of fibrosis and hyalinization in and around MSG resulting in reduced secretion of mucins (insulators) [18] at the tips of microplicae (oral mucosal barrier complex) of superficial cells of the oral epithelium [19]. This results in decreased salivary mucus gel (SMG) production leading to SMG barrie\r loss producing the following consequences [17]: In OSMF, normal physiologic friction results in rapid exfoliation of superficial cells of the oral epithelium owing to less protection leading to epithelial atrophy. The surface is further sensitive to burning sensation as a result of decrease in the distance of intra-epithelial nerve endings from the surface. Furthermore, burning sensation is also because of spicy food elements diffusing easily towards intra-epithelial nerve endings as a result of diminished defensive diffusion membrane (DDM) function of SMG [17]: lesional keratinocytes showed nuclear positivity for phosphorylated SMAD2, suggesting the role of transforming growth factor beta (TGF-b1) in inhibiting the epithelial growth and thereby causing pronounced epithelial atrophy in OSMF [20];
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G2/M cell cycle arrest and increased sub-G0/G1 population is a hallmark of apoptosis caused by arecoline. The impairment of vascular function through endothelial damage possibly contributed to the pathogenesis of OSMF [21]. This reflected the reduced vascularity witnessed in histological sections of OSMF as the disease advanced. This led to atrophy of the epithelium and a hypoxic environment is created predisposing to carcinogenesis [20]. the likelihood of cytotoxic and genotoxic effects of inducible nitric oxide synthase(iNOS) on adult stem cell pools of epithelium due to it’s expression and over activity in OSMF probably leads to epithelial thinning [22]; cytokeratin-18 (CK18) which is used to assess the level of cell multiplication is probably related with epithelial atrophy of OSMF [23]; the anterior region of the mouth (has most prominent connective tissue papillae) has greater density of sensory receptors than the posterior region [24]. So it is possible that burning sensation is felt more in the anterior than in the posterior area of the mouth on consuming spicy food. lastly, adding on the biochemical functions of vitamin A, it is essential to maintain a healthy epithelial tissue. Further, retinyl phosphate is essential for the formation of mucopolysaccharides, compounds of mucus secreted by the epithelial cells to maintain a moist surface [25]; previous studies have found reduced serum vitamin A levels in OSMF patients. Mucous membranes are stabilized by vitamin A as its deficiency results in loss of mucous secreting cells and epithelial atrophy leading to mucosal irritation. Reduced bioavailability of vitamin A in OSMF mirrored its increased consumption to scavenge lipid peroxidation product, malondialdehyde (MDA) which is increased in OSMF [26]. All the above factors possibly play a role in atrophy of the epithelium resulting in burning sensation on consuming spicy food in these patients. 5.3. Restricted mouth opening It is one of the most imperative presenting symptom as well as sign in the later clinical stages which hampers the patient in consuming food thus leading to cachexia and possibly death. 5.4. Aetiopathogenesis Arecanut alkaloids causes chemical injury to the buccal mucosa provoking a defensive inflammatory response. This continuous process of arecanut chewing leads to chronic inflammation [27]. In certain inflammatory diseases, prostaglandin synthesis is brought about by an enzyme, COX-2. In OSMF, epithelial cells, fibroblasts and inflammatory cells revealed strong immunostaining for COX-2. This suggests that chronic inflammation triggered by arecolineinduced cell injury is customarily followed by excessive fibrosis [14]. In response to injury, several inflammatory mediators such as prostaglandin E2 (PGE2), interleukin 6 (IL-6), tumour necrosis factor-alpha (TNF-a) and more outstandingly TGF-b are secreted by keratinocytes [20]; The regulation of inflammatory reaction as well as transcriptions of collagen and collagenase is brought by TNF-a which facilitates multiple functions [28];
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TGF-b favours collagen production by moderating three main events: triggering of procollagen genes, raising procollagen proteinases levels, lysyl oxidase (LOX) activity is up regulated [27]. in OSMF, there is striking up-regulation of avb6 integrin which triggers TGF-b1, the key modulator of tissue fibrosis. TGF-b1 causes trans-differentiation of oral fibroblasts into myofibroblasts facilitating matrix accumulation by increasing the deposition of matrix proteins mainly in the form of collagen I and decreasing the degradation of matrix proteins by upregulating the tissue inhibitor of matrix metalloproteinases (TIMP-1) gene [20]; a review described the pathogenesis of OSMF in detail with special emphasis on copper [29]. LOX is a copper-dependent enzyme, vital for the cross-linking of collagen and elastin [30]. producing insoluble collagen that is unaffected by proteolysis [27]. The copper content of arecanut is high and the up regulation of LOX [31] suggests it’s possible role in fibrogenesis [30]. ROS elicited by arecoline-induced cell injury triggers nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), c-Jun N-terminal protein kinase (JNK) and p38 mitogenactivated protein kinase (MAPK) with subsequent connective tissue growth factor (CTGF) expression in buccal mucosal fibroblasts. It is possible that the fibrotic activity in OSMF is enhanced by overexpression of CTGF and basic fibroblast growth factor (bFGF) [32] thus playing a role in the pathogenesis [20]; one study found that as histopathological grades of OSMF progressed, the levels of tissue MDA decreased which possibly reflected its consumption in cross-linking of collagen [33]; TGF-b reduces the collagen degradation by moderating two main events: TIMP-1 gene is triggered and thus impedes activated collagenases; triggering of plasminogen activator inhibitor (PAI) gene. Consequently, plasmin is not produced for active collagenase formation [27]. there is down regulation of the main human enzyme matrix metalloproteinase-1 (MMP-1) which degrades fibrillar collagen and also bone morphogenetic protein 7 (BMP7, negative modulator of fibrosis) leading to increased deposition of collagen in OSMF [20]; fibroblast phagocytosis is suppressed by arecoline leading to OSMF [34]. Weakening of the immunity ensues as a result of inhibition of T cell activity by arecanut extracts [35]. Continuous accretion of collagen with triggering of signaling pathways such as ALK5, JNK, SMAD and p38 MAPK is contributed by TNF-a, bFGF and CTGF while the chief mediator of OSMF seems to be TGF-b [20]. All the above factors seem to play a pivotal role in restricted mouth opening seen classically in higher clinical stages of OSMF.
6. Role of ALA in OSMF 6.1. Improved GSH levels Incessant antioxidant activities are executed efficiently by vitamin A and C which is mediated by the most indispensable and potent antioxidant, glutathione. Neutralization of the free
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radicals leads to consumption of antioxidants. Antioxidants become active afresh when they return to their standard electron configuration and this is brought about by reduced glutathione. Thus, the antioxidant levels in the body are upheld by GSH. Execution of various functions results in diminution of reduced glutathione [10]. Intracellular levels of glutathione is improved by ALA administration [36] and glutathione is reduced and regenerated by DHLA [11]. Thus ALA probably intercepts the conversion of lower clinical stages of OSMF into higher ones. 6.2. Resolvement of burning sensation As mentioned previously, intracellular levels of glutathione is improved by ALA administration [36] and glutathione aids vitamin A in performing it’s antioxidant activities efficiently [10]. Thus, the integrity of the epithelium is maintained reducing it’s atrophy and ensuing burning sensation. As ALA and DHLA quenches the free radicals, TGF-B1 as well as iNOS are probably not expressed. As a result perhaps there is no more inhibition of the epithelial growth(epithelial thinning) thereby reducing epithelial atrophy and ensuing burning sensation. Also, ALA possibly acts as a neuroprotective agent thus reducing burning sensation of the oral mucosa [37]. 6.3. Progress in mouth opening In a study, patients treated with ALA and intralesional injections of steroids and hyaluronidase showed reduced burning sensation of the oral mucosa and progress in mouth opening values as compared to the group treated with intralesional injections alone [38]. 6.4. Probable mechanism of action As LOX is a crucial enzyme in inducing fibrogenesis, curbing the activity of LOX by using a copper chelator may help in reducing the fibrosis by preventing cross-linking of the collagen fibers [27]. Redox-active metals like copper are chelated by ALA and its reduced form, DHLA functioning as ROS scavengers as well as copper chelators [11]. So probably there is reduction of further process of fibrosis. Improved mouth opening also appears to be due to the improved levels of glutathione whose depletion has an important role in the pathogenesis of fibrosis. Intracellularly, glutathione is the main redox buffering thiol playing an essential role in lymphocytic function and activation of T-cells [37]. Thus probably, the cell mediated immunity and phagocytic activity of the cells are improved resulting in collagen degradation. Glutathione-aided vitamin A functions efficiently in scavenging MDA leading to possible prevention of crosslinking of collagen. One study found reduced plasma levels of IL-6 protein (proinflammatory cytokine) by ALA administration resulting in subdual of the inflammatory process [39]. Proinflammatory cytokines such as TNF, triggered molecular signaling pathways leading to inflammatory response which was inhibited by ALA [11]. So, the most crucial step that is, the inflammatory process is halted by ALA making it perhaps an effective anti-inflammatory agent as well. Also as chronic inflammation is invariably followed by fibrosis, further inflammation and subsequent fibrosis may be prevented by ALA as it quenches peroxynitrite radicals. NF-kappa B, JNK and p38 MAPK pathway is probably blocked as a result of ROS scavenging by ALA and thus subsequent prevention of CTGF overexpression.
It was shown that for hypoxia-induced TGF-b1 up regulation, ROS was essential [20]. As ROS is scavenged by ALA, TGF-b1 and TIMP-1 is probably not expressed(down regulated) and MMP-1 is no longer down regulated. All these probably are the reasons for an improved mouth opening observed in the study mentioned above. 6.5. Possible prevention of carcinogenesis OSMF is one of the most common amongst PMDs, frequently heralding oral squamous cell carcinoma (OSCC) [9]. In arecanut chewers, primary oral keratinocytes may initiate inflammation of the buccal mucosa by production of PGE2, TNF-a and IL-6 leading to OSMF and contributing to the pathogenesis of cancer by marring T cell activation [40]. A study confirmed striking up regulation of hypoxia-inducible factor 1-alpha (HIF-1a) and attendant epithelial dysplasia and progression in fibrosis in OSMF samples suggesting it’s possible role in malignant transformation [41]. Migration of the keratinocytes and initiation of invasion is stimulated by arecoline-dependent avb6 up-regulation probably indicating its’s part in malignant transformation (more than 80%) [42]. Disparity between the existence of ROS and CADS creates oxidative stress which is observed in OSCC [43]. Substantial proof advocates that the inhibition of both initiation and promotion of carcinogenesis is performed by antioxidant enzymes. Progression of cancer is due to the low activities of these enzymes [44]. One study found that the serum and salivary total antioxidant capacity levels decreases as severity of OSMF increases [45]. The premalignant potential of OSMF may be allied with its reduced serum levels of GSH-Px and SOD in such patients [3]. Reduction of antioxidants and formation of oxidative stress like milieu in OSMF patients is due to the diminution in plasma GSH levels [10]. These patients are incapable of scavenging ROS [10] thus contributing to carcinogenesis as ROS and free radicals are implicated in malignant transformation [9]. 6.6. Probable mechanism of action ALA is supposed to augment the functional life span and preserve the genomic and structural integrity of mitochondria by guarding it against respiration-linked oxidative stress. NF-B pathway for which TNF is a key activator mediates inflammatory responses and regulates expression of several inflammatory mediators. NF-B also activates COX-2 and iNOS involved in inflammatory process. Molecular signaling pathways activated by proinflammatory cytokines such as TNF is inhibited by ALA by suppressing the inflammatory response which is crucial in carcinogenesis [11]. ALA helps in the inhibition and management of oxidative stress facilitated pathological disorders as enormous amounts of free radicals are quenched by it [11]. Thus, ALA may also be beneficial in OSMF which is in itself another classic example of an oxidative stress situation. Also as ALA quenches ROS and improves intracellular GSH levels which is an important antioxidant enzyme, it might play a vital role in prevention of carcinogenesis in OSMF patients. ALA is a natural antimutagene exhibiting antimutagenic and anticarcinogenic actions, exemplifying a prospective therapeutic agent for the vascular endothelium [11]. Also, as mentioned previously, ALA probably controls fibrosis in the connective tissue by acting mainly as a ROS scavenger and copper chelator leading to possible improvement in the vascula-
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ture reducing hypoxia and subsequent risk of developing epithelial dysplasia. 7. Conclusion The inference of oxidative stress in the etiology of OSMF suggests that antioxidant therapy such as ALA perhaps epitomizes a healing touch in the path of management. The role of ROS is noteworthy in both pathogenesis and malignant transformation of OSMF. Therefore, momentous therapeutic benefits are offered by antioxidants in managing the disease and preventing its malignant transformation. Intralesional injections of steroids and hyaluronidase have shown proven success in mouth opening; but as substantial pain, discomfort etc follows, ALA appears promising in the management of OSMF alone or as an adjunct thus minimizing the overall treatment time. More studies should be conducted in higher clinical stages so that ALA may be used as a first line therapy in medical management. Future directions should aim at conducting further studies to confirm the benefits of ALA in OSMF and especially its role in the prevention of malignant transformation in these patients. Meanwhile, these patients should be advised to do regular mouth opening exercises and to be cautious about the various clastogenic habits such as consumption of arecanut, tobacco in any form, alcohol and motivated to stop the habit which in itself must be the first line of management. Ethical statement We, the authors of this manuscript state that the manuscript has been read and approved by us and that the requirements for authorship have been met, and we believe that the manuscript represents honest work. I, Dr Gowri located and selected the articles, and acquired and analysed the data. Both I, Dr Gowri, Dr Kushal and Dr Arati drafted the article, prepared the manuscript and revised it. Final approval of the version to be published is given by myself Dr Gowri, Dr Kushal and Dr Arati. Role of the funding source Nil. Disclosure of interest The authors declare that they have no competing interest. References [1] Kamath VV, Satelur K, Komali Y. Biochemical markers in oral submucous fibrosis: a review and update. Dent Res J 2013;10:576–84. [2] Warnakulasuriya S, Johnson NW, Van der Waal I. Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med 2007;36:575–80. [3] Uikey AK, Hazarey VK, Vaidhya SM. Estimation of serum antioxidant enzymes superoxide dismutase and glutathione peroxidase in oral submucous fibrosis: a biochemical study. J Oral Maxillofac Pathol 2003;7:44–5. [4] Tilakaratne WM, Klinikowski MF, Saku T, Peters TJ, Warnakulasuriya S. Oral submucous fibrosis: review on aetiology and pathogenesis. Oral Oncol 2006;42:561–8. [5] Patel JB, Shah FD, Shukla SN, Shah PM, Patel PS. Role of nitric oxide and antioxidant enzymes in the pathogenesis of oral cancer. J Cancer Res Ther 2009;5:247–53. [6] Biewenga GP, Haenen GR, Bast A. The pharmacology of the antioxidant lipoic acid. Gen Pharmacol 1997;29:315–31. [7] Gupta S, Reddy MVR, Harinath BC. Role of oxidative stress and antioxidants in aetiopathogenesis and management of oral submucous fibrosis. Indian J Clin Biochem 2004;19:138–41. [8] Pham-Huy LA, He H, Pham-Huy C. Free radicals, antioxidants in disease and health. Int J Biomed Sci 2008;4:89–96.
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Please cite this article in press as: Bhandarkar GP, et al. Thioctic acid in oral submucous fibrosis (India’s disease) – A better tomorrow. J Stomatol Oral Maxillofac Surg (2017), https://doi.org/10.1016/j.jormas.2017.12.006