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REVIEW ARTICLE
Year : 2014  |  Volume : 4  |  Issue : 4  |  Page : 198-202

Future prospective and current status of antioxidants in premalignant and malignant lesions of oral cavity


Department of Oral Medicine and Radiology, Institute of Dental Studies and Technologies, Modinagar, Uttar Pradesh, India

Date of Submission10-Mar-2014
Date of Acceptance16-Apr-2014
Date of Web Publication22-Aug-2014

Correspondence Address:
Shalu Rai
C 1 Sector 23, Noida 201 301, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2231-0738.139399

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   Abstract 

In the late 19 th and early 20 th century, extensive study was devoted to the use of antioxidants in important industrial processes, such as the prevention of metal corrosion, vulcanization of rubber, and polymerization of fuels in the fouling of internal combustion engines. In recent years, there is an upsurge in the areas related to newer developments in prevention of disease, especially the role of free radicals and antioxidants. So it will be pertinent to examine the possible role of 'free radicals' in disease and 'antioxidants' in its prevention. Antioxidants are intimately involved in the prevention of cellular damage-the common pathway for cancer and a variety of diseases. The reversal or suppression of premalignant lesions is an important strategy against carcinogenesis for the prevention of cancer. Whether antioxidants can protect the human population from diseases like leukoplakia, lichen planus, carcinoma in situ or oral cancer and also from cancers of the upper aero digestive tract i.e. larynx, pharynx and esophagus and increase the life expectancy is still controversial. This article deals with the action of various chemopreventive agents along with brief review of literature about the outcome of effect of antioxidant on potentially premalignant and malignant lesions of oral mucosa.

Keywords: Antioxidants, free radicals, leukoplakia, lichen planus, oral cancer


How to cite this article:
Rai S, Malik R, Misra D, Sharma A. Future prospective and current status of antioxidants in premalignant and malignant lesions of oral cavity. Int J Nutr Pharmacol Neurol Dis 2014;4:198-202

How to cite this URL:
Rai S, Malik R, Misra D, Sharma A. Future prospective and current status of antioxidants in premalignant and malignant lesions of oral cavity. Int J Nutr Pharmacol Neurol Dis [serial online] 2014 [cited 2019 Oct 18];4:198-202. Available from: http://www.ijnpnd.com/text.asp?2014/4/4/198/139399


   Introduction Top


Great debates have sometimes spawned great breakthrough in medical treatment, improving patient outcomes and saving lives. One such debate that has long-loomed is the use of antioxidant therapy in day-to-day medicine.

Free radicals induced oxidative damage has been implicated in most inflammatory and degenerative diseases. [1] Scientific research has shown that antioxidants may play a role in the etiology of cancer, while antioxidant-containing fruits and vegetables may protect against some of these diseases, the role of supplemental antioxidants in the prevention of chronic illnesses remains unproven. [2]

Antioxidants have been proposed to be useful in the chemoprevention and management of various precancerous lesions and other free radical related diseases.


   Discussion Top


Antioxidants can be better understood by having information about their nature and reactivity of reactive oxygen species or free radicals. [3]

Classification of free radicals

First classification . [4] Examples of free radicals include sigma, pi-delocalized, carbon-centered, oxygen-centered, sulfur-centered, nitrogen-centered, reducing radicals, oxidizing radicals.

Second classification[5]

  • Hydroperoxyl (per hydroxyl) radical
  • Superoxide radical
  • Hydrogen peroxide
  • Singlet oxygen and triplet oxygen.


Mechanism of action of free radical

Free radicals are formed by dissociation of neutral molecule generating two free radicals or loss or addition of single electron to neutral molecule. [5]

Antioxidants

Antioxidants may be regarded as those substances which will significantly delay or inhibit the oxidation of a substance and protect the body against oxidative damage. [6]

Classification of antioxidants

First classification [7]

Enzymatic antioxidants examples include superoxide dismutase, malondialdehyde, glutathione peroxides, catalase, glutathione reductase, glutathione transferase.

Non-enzymatic antioxidants: Examples include

Nutrient-alpha tocopherol, beta carotene, vitamin A, vitamin E, acorbate, glutathione, selenium

Non-nutrient - ceruloplasmin, transferrin, uric acid, peptides camosine.

Second classification[5]

Natural antioxidants - they can be divided into following categories:

Enzymes-examples include superoxide, hydroxyl and glutathione peroxidase

Low molecular weight antioxidants-they are further subdivided into

Lipid-soluble antioxidants, which include tocopherol, carotenoids, bilirubin and some polyphenyls

Water-soluble antioxidants, which include ascorbic acid, uric acid and polyphenyls.

Synthetic antioxidants are synthetic chemicals, which include butylated hydroxyl anisole, butylated hydroxyl toluene and tertiary butylated hydroxyl quinine.

Mode of action

The antioxidants act by breakage of chain reaction, reducing concentration of reactive oxygen species, scavenging initiating radicals or chelation of transition metal catalyst. [5]

Various antioxidants

Uric acid: It has been suggested that uric acid and its derivatives provide protection against certain oxidizing agents such as ozone [8]

Melatonin: It functions as a non-enzymatic free radical scavenger that donates an electron (as hydrogen) to neutralize free radicals [9]

Coenzyme q10 (ubiquinone): It is a lipid-soluble pro vitamin that is structurally similar to vitamin K [10]

Vitamin A, beta carotene and retinoids: Retinoids are synthetic form of vitamin A. Beta carotene is a vitamin A precursor. It regulates epithelial differentiation and has a direct action on intercellular cohesion and interaction. It inhibits the malignant transformation. It influences different types of immunity [11]

Lycopene: It is a carotenoid without pro vitamin A activity. It binds to chemical species that react to oxygen. It is suggested to have anti-cell-proliferative and anti-carcinogenic activities [12]

Ascorbic acid : It is also known as vitamin C and has the ability to regenerate alpha tocopherol from the tocopherol radical that forms at membrane surfaces [11]

Vitamin E: Alpha-tocopherol is the most active form of vitamin E. It stabilizes the structural integrity of cell membranes by protecting them from liquid peroxidation and enhances immune response by increasing the mitogenic response. [11]

Other antioxidants

Alpha lipoic acid

It plays an important role in controlling blood sugar, repair of nerve tissue, blindness, heart disease, protection of liver, detoxification of the body from heavy metal pollutants and accelerated aging. Recently, it has been found to be effective in patients with burning mouth syndrome. [13]

Catechins and flavonoids are the most significant antioxidants in tea. Black tea possesses antioxidant property comparable to green tea. It can also decrease low density lipoprotein (LDL) cholesterol, having protective action against cancer, heart diseases and stroke. Topical application of green tea extract has shown to reduce thickness of oral leukoplakia. [14],[15]

Curcumin

It is found in turmeric and gives protection against environmental dietary mutagens. Frequently used spices and herbs as antioxidants are rosemary, sesame seeds, pepper, chilli pepper and ginger. Garlic powder has been shown to inhibit cancer development in different spices and at different sites or organs. [16]

Spirulina, a 95% digestible blue green algae, also called green blood consists of vitamin A, B complex, E, chelated products of K, Ca, Mg, Zn, P, Fe, Se and 9 cis isomer. It is believed to have powerful antioxidant properties and is used in oral precancerous lesions and conditions. [17]

Oral oxidants and antioxidants

Oral oxidants lead to transformation of a normal cell into neoplastic cell. This is a very slow process and proceeds through initiation, promotion and progression of disease. Saliva in the oral cavity contains number of nutrients and microorganisms and it is constantly exposed to a variety of oxidants. To counter the toxic effects of these oxidants, saliva has antioxidants like uric acid, ascorbate, reduced glutathione and alpha tocopherol, which are delivered to saliva through the crevicular fluid of gingiva. Additional sources of antioxidants in the oral cavity are catalase-positive commensal and fresh blood from injured capillaries. Blood from gingival hemorrhage contains both oxidants like toxic iron-catalyzed hydroxyl radical and oxygen-scavenging abilities (OSA) as antioxidant, which protects other cells of oral cavity from oxidative stresses. It has been proven that red blood cells (RBC) binds with a variety of antioxidant polyphenols from nutrients increasing their OSA. Red blood cells coated by polyphenols, further act with salivary low molecular weight antioxidants (LMWA) to enhance the scavenging of reactive oxygen species, both acting as solubilizers of polyphenols making them antioxidants that are more effective. [18] Deficiency of beta carotene can lead to periodontal destruction. Prostaglandin inhibitory effect of alpha tocopherol contributes in reducing periodontal inflammation. Vitamin C deficiency leads to bleeding of gums. Turmeric or curcumin has antibacterial and fungicidal properties. Epigallocatechin-3-gallate found in green tea reduces the risk of dental caries and plaque formation and is also effective in oral leukoplakia. [19] Continuous advancement in laboratory techniques help in better understanding of process of carcinogenesis. Enzymatic and non-enzymatic antioxidants like vitamin A, beta carotene, vitamin E, malonaldehyde and superoxide act together to detoxify the effects of these oxidants, which cause cell damage and may even lead to oral premalignant and malignant disorders. [19],[20]

Antioxidant therapy for leukoplakia

Silverman SJR, Kaugars GE in their study used 13cRA in the range of 0.5 to 1 mg/kg/d as a starting dose for the treatment of premalignant oral lesions. For patients presented with an extensive premalignant oral lesion, it was advisable to begin with 50 mg of 13-cRA/d. The maximum duration of continuous 13-cRA is 3 months. They also found more than a 50% reduction in the clinical size of the lesion with 13-cRA. [20] Shah et al., treated 16 patients with oral leukoplakia with topical doses of 13-cRA, which ranged from 3 to 10 mg/day for 6 months delivered by lozenges. Five (31.2%) of the patients dropped out because of the side-effects, and 2 of the 3 patients who showed complete clinical resolution had recurrences within 5 weeks of discontinuing the medication. [21] Hong WK, Endicott J et al., in their placebo-controlled double-blind study demonstrated two key points: The toxicities associated with high-dose 13-cRA were frequent and severe, and remission was brief, that is within 3 months of therapy cessation, more than half of the patients experienced a relapse. [22] Stich HF, Rosin MP, and Hornby AP et al., tested combined beta-carotene and retinol, beta-carotene alone, and placebo, in oral leukoplakia, which produced complete response rates of 27.5%, 14.8% and 3.0%, respectively. [23] Kaugars et al., Benner et al., reported a multicenter study showing a response rate of 46% in 43 subjects treated with 400IU vitamin E twice daily for 24 week, which was found to be active in reversing oral leukoplakia. [24],[25] Kaugars et al., said that the use of multiple antioxidants in the treatment of oral leukoplakia is debatable because of their differences in sub-cellular distribution and efficiencies at variable oxygen pressures. However, patients who had never used alcohol or tobacco also demonstrated a reduction in the size of the oral leukoplakia. [24]

Lippman SM, Batsakis JG et al., conducted a trial to assess the toxicities and short-lived remissions with use of high-dose 13-cRA. The 13-cRA group demonstrated 33% reduction in the lesion, whereas 10% in the β-carotene group. [26] The treatment of hyperkeratosis or atypical hyperplasia with 13-cRA is difficult to justify because of the chances of transformation into carcinoma, the high percentage of side effects, and the recurrences noted after the 13-cRA is discontinued.

Antioxidant therapy in oral lichen planus

Hersle K, Mobacken H, Sloberg K used etretinate in patients with oral lichen planus. Recurrences were noted in many patients after discontinuation. They prescribed etretinate 75 mg to 10 patients with erosive lichen planus over a period of 8 weeks. [27] Petruzzi M et al., used tazarotene for the treatment of lichen planus. Tazarotene has an effect on the growth and differentiation of keratinocytes in psoriasis. Tazarotenic acid has a half-life of 1-2 hours; and therefore, no systemic monitoring is necessary and no side effect has been reported in over 2000 patients previously enrolled in clinical trials. Mouth soreness and transient erythema have been documented. [28]

A study evaluated the effectiveness of antioxidant-rich purslane in the treatment of oral lichen planus. A total of 37 biopsy-proven symptomatic OLP patients were selected for this randomized double-blind placebo-controlled trial. All subjects were divided into two groups to receive purslane (n = 20) or placebo (n = 17) for 3 months. Assessments were made at baseline, after 2 weeks and each month for 6 months, based on the visual analog scale (VAS) and clinical improvement including lesion type and size. Approximately 83% of the purslane patients showed partial to complete clinical improvement but 17% had no response. [29]

Antioxidant therapy in oral sub mucous fibrosis

Borle et al., reported that vitamin A, 50,000 IU chewable tablets, if given once daily could cause symptomatic improvement with no improvement in trismus. [30] Maher et al., evaluated the role of multiple micronutrients consisting of retinol, vitamin E, vitamin D, vitamin B complex and some minerals in the management of oral sub mucous fibrosis (OSMF) and reported clinical improvement. [31] Roth et al., have shown that turmeric has a beneficial role in treatment of OSMF. It has been found to have effective antioxidant properties, DNA- protectant and anti-mutagenic actions. [32] Soma gupta et al., assessed the non-enzymatic antioxidant defence status of the body in a study by plasma β-carotene and vitamin E level, β-carotene level was decreased in all grades of OSMF cases. [33]

Role of antioxidants in oral cancer

Ames, suggested that antioxidants produce cancer regression, inhibition of metastasis and prevention of carcinogenisis. [34] Chen et al., examined the relationship of sex specific mortality rates for selected cancers with the biochemical indicators of antioxidant status including sod, catalase and found that the plasma levels of antioxidant enzymes were negatively correlated with cancer mortality rates. [35] Casado et al., found the sod activity in patients with cancer was not different from the SOD activity observed in the normal population. [36] According to Shklar, [37] antioxidants have the ability of destroying cancer cells through immuno enhancement, molecular genetics pathway and depression of tumor angiogenesis activity. They found tumor cells to be low in superoxide dismutase (SOD) and catalase activity compared with normal tissue. Hristozov et al., found significantly higher levels of lipid peroxidation products (malonaldehyde) in early and advanced cancers in comparison to controls. [38] Das, suggested that tumor cells have relatively low amounts of SOD, which quenches superoxide anion and as a result of a higher level of aerobic metabolism, higher concentration of hydroxyl ion compared with normal cells. He also suggested that ionizing ration radiation and chemotherapeutic agents like anthracyclines and bleomycin exert their anticancer effect by the producing free radicals. [39]


   Conclusion Top


Low levels of antioxidants cause oxidative stress and may damage or kill cells. As oxidative stress appears to be an important part of many diseases, it is both the cause and the consequence of disease. Oxidative stress plays a major role in the pathogenesis of many diseases of oral cavity including aphthous ulcer and oral lichen planus also. [40],[41] The use of antioxidant have been widely used as dietary supplements and have been investigated for the prevention of diseases such as cancer, coronary heart disease, potentially malignant oral mucosal lesions and conditions. The scientific community has begun to unveil some of the mysteries surrounding this topic, and the media has begun whetting our thirst for knowledge. Thus we conclude that antioxidants provide basis of chemoprevention in subjects at risk of developing oral premalignant and malignant conditions.

 
   References Top

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