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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 7  |  Issue : 3  |  Page : 72-78

Prevention of oral cancer by natural products


1 Professor, Department of Oral Maxillofacial Surgery, Al-Farabi Private Colleges, Jeddah, Saudi Arabia
2 Doctor, Department of Oral Maxillofacial Surgery, Al-Farabi Private Colleges, Jeddah, Saudi Arabia
3 Intern Student, Department of Oral Maxillofacial Surgery, Lithuanian University of Health Science, Kaunas, Lithuania

Date of Submission08-Jun-2020
Date of Acceptance23-Jun-2020
Date of Web Publication29-Sep-2020

Correspondence Address:
Dr. Mohamed Yaser Kharma
Al-Farabi Private Colleges, Department of Oral Maxillofacial Surgery, Jeddah
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/INPC.INPC_22_20

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  Abstract 


Oral cancer has a tendency to be detected at late stage which is detrimental to the patients because of its high mortality and morbidity rates. Early detection of oral cancer is important to reduce the incidence of mortality. The use of natural products which have a rich source of anticancer agents helps to reverse, suppress, or prevent carcinogenic progression. Chemopreventive agents play a crucial role in reversal, suppression, and prevention of carcinogenesis of premalignant or malignant cells by modulating cell proliferation or differentiation. This article review describes the most important chemopreventive agents taking place in the prevention of premalignant lesions to develop to oral cancer. By including cancer fighting foods in the daily diet like leafy green vegetables, sweet potatoes, carrots, soya, seaweed, drumsticks, tomatoes, grapes, avocado, grapefruit, papaya, lemon, oranges, and green tea, oral cancer can be prevented. Natural therapies may be a good substitute in the prevention of premalignant lesion to develop to invasive cancer by using Chemotherapeutic agents.

Keywords: Antioxidant, chemoprevention, chemotherapeutic, oral cancer, premalignancy


How to cite this article:
Kharma MY, Koussa B, Dadoue M, Daboul M, Hasan R, Daboul R, Muhsin M. Prevention of oral cancer by natural products. Int J Prev Clin Dent Res 2020;7:72-8

How to cite this URL:
Kharma MY, Koussa B, Dadoue M, Daboul M, Hasan R, Daboul R, Muhsin M. Prevention of oral cancer by natural products. Int J Prev Clin Dent Res [serial online] 2020 [cited 2020 Oct 24];7:72-8. Available from: https://www.ijpcdr.org/text.asp?2020/7/3/72/296535




  Introduction Top


Oral cancer is one of the usual causes of mortality all over the world, with a 5-year survival rate of only 50%. Oral cancers are treated primarily by surgery with/without adjuvant radiotherapy and/or chemotherapy.

Oral carcinogenesis is a multistep process accompanied by genetic changes, which lead to progressive dysplasia, unregulated cell growth, and cancer. Nearly 75% of oral cancers are related to lifestyle choices. The distribution of oral cancer is approximately 32% in buccal mucosa, 22% in tongue, 11% in lower lip, 11% in palate, 8% in vestibule, 5% in alveolus, 5% in floor of the mouth, and 3% in gingiva.[1]

Cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells. It is caused by both external factors (tobacco, chemical, radiation, and infectious organisms) and internal factors (hormones, inherited mutations, immune conditions, and mutations that occur from metabolism). Cancer is potentially one of the most preventable and curable life-threatening diseases. It is the second major cause of deaths after cardiovascular diseases.[2]

The risk factors are many including smoking, betel nut and tobacco chewing, drinking, poor nutrition, human papilloma virus (HPV), mouth washes with a high alcohol content, poor oral hygiene, immune system suppression, age, and gender. Other risk factors include genetic factors, mate drinking, and chronic trauma.[3],[4]

Oral cancer follows the molecular progression model in specific molecular events, including oncogene activation and inactivation of tumor suppressor genes, leading to progression from normal cell growth to frank neoplasia and tumor formation.

As they are asymptomatic at the earlier stages, detection of oral cancer becomes difficult. Diagnosis at the earliest stage is, therefore, very important for increasing the rates of patient survival. The survival rates are approximately 80%–90% when detected at the earliest.[5]

Advance screening methods employed is for early detection and prediction of oral cancer, which helps to locate the oral cancer and helps in early diagnosis.[6]


  Chemoprevention: A New Way to Prevent Oral Cancer Top


The administration of an agent to stop a cancer from occurring is known as chemoprevention. The agent can be a natural product or a drug.[7] Chemopreventive agents are chemicals or substances, which have anticancer properties. Most of the compounds used in cancer chemoprevention studies are natural phytochemicals present in food.[8]

In 1976, Michael B. Sporn coined the term chemoprevention and defined it as the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent carcinogenesis before the development of invasive malignancy.[9] The term chemoprevention includes prevention of initiation, promotion, and progression of carcinogenesis to cancer.[10]

In order to reduce the incidence of oral cancer, early diagnosis and prompt treatment of the potentially malignant disorders is necessary. Therefore, natural therapies may be a good substitute. Hence, the role of preventive strategies could be a major breakthrough in the management of oral cancer.

Undoubtedly, chemopreventive agents play a crucial role in the reversal, suppression, and prevention of carcinogenesis.[10]


  Categorization of Preventive Measures of Oral Cancer: Primary, Secondary, and Tertiary. Top


The goal of primary preventive measure is to increase public awareness regarding the risk factors. Primary prevention is stoppage of risk factor exposure, such as tobacco, and includes educating the general population about the potential ill effects associated with tobacco and counseling patients about the risk factors associated with oral cancer.[11]

Secondary prevention aims at the detection and early diagnosis of premalignant lesions through advance screening techniques. Secondary prevention involves patients who have known potentially malignant lesions (i.e., oral leukoplakia) and attempts to prevent the progression of the premalignant lesions into cancers. Chemopreventive agents are directed toward secondary preventive stage where appropriate action can be directed toward early precursor lesions such as leukoplakia. Intervention at this stage will reduce the morbidity and mortality associated with the oral cancer. Oral cancer prevention essentially involves reversal or suppression of the carcinogenesis process. Chemoprevention is defined as the administration of agent (s) to block or reverse carcinogenesis. Chemoprevention in oral cancer has been directed toward reversing premalignant lesions and preventing second primary tumors.

Tertiary prevention aims at preventing the redevelopment of oral cancers in patients. Tertiary prevention focuses on the prevention of second primary tumors in patients treated for cancer. Tertiary prevention involves reduction of complications, prevention of further dysfunction, and reduction of long-term complications of disease, including speech, dental, and swallowing problems.[12]


  Classification of Chemopreventive Agents According to Their Function Top


  1. Antimutagens/carcinogen blocking agents
  2. Antiproliferative/carcinogen suppressor
  3. Antioxidants.[13]


Antioxidants are substances that can inhibit the process of oxidation associated with free radicals. Free radicals are oxidants that are unpaired electrons, which are highly active and are thought to interact with DNA causing cell damage and cancer.[14]


  Classification of Chemopreventive Agents According to Their Categories Top


These chemopreventive agents were broadly classified into the following four categories: hormonal chemopreventive agents, medications, diet-related agents, and vaccines.[9]

Hormonal chemopreventive agents

  • Anti-estrogens: They are effective for reduction of the risk of invasive breast cancer in postmenopausal women
  • Anti-androgens: They are most commonly used for the treatment of prostate cancer.[15]


Medications

  • Aspirin: Aspirin is a nonsteroidal anti-inflammatory drug, which causes an irreversible inactivation of cyclooxygenase-1 (COX-1) and COX-2. A randomized controlled trial revealed that dosage of aspirin 81–325 mg reduces the risk of head-and-neck cancer by 22% through inhibition of COX-2 and downstream biological pathways, such as nuclear factor-κB (NF-κB) signaling in carcinogenesis[16]
  • Indomethacin: Indomethacin presents antineoplastic activity at low doses. A study by Lundholm et al.[17] has stated that indomethacin 50 mg twice daily can significantly extend the survival of patients with metastatic disease due to its inhibitory activity on prostaglandin E2 levels, which in turn inhibits cell growth
  • Capsaicin: Capsaicin possesses analgesic, antioxidant, anti-inflammatory, anti-obesity, anti-invasive, and anti-migratory properties. It induces apoptosis in many types of cancer cell lines while leaving normal cells unharmed[18]
  • Lovastatin: Lovastatin is primarily used for the treatment of dyslipidemia, treatment of hypercholesterolemia, and prevention of cardiovascular diseases. Lovastatin reduces cellular proliferation and induces apoptosis in cancer cells. A study by Knox et al.[19] has found that oral administration of lovastatin 7.5 mg/kg daily for 21 days and repeat therapy for every 28 days is effective against squamous cell carcinoma of head and neck and cervix with no adverse effects on renal function
  • Atorvastatin: Atorvastatin is used to treat high cholesterol and to lower the risk of stroke, heart attack, or other heart complications in people with Type 2 diabetes, coronary heart disease, or other risk factors. Atorvastatin exhibits antitumorigenic activity in cancer cells through induction of apoptosis, cell-cycle G1 arrest, and autophagy, resulting in reduced cell proliferation. Oral administration of atorvastatin 20 mg/night for 2 years during radiotherapy was found to be effective in nasopharyngeal carcinoma with no reported side effects[20]
  • Metformin: Metformin is an oral diabetes medicine that helps control blood sugar levels. Metformin exhibits an indirect antineoplastic effect through an insulin-dependent pathway. A study by Curry et al.[21] has found that oral administration of metformin 500–2500 mg daily in patients with diabetes is effective in head-and-neck squamous cell carcinoma (HNSCC) by inducing the apoptosis of carcinoma cells
  • Taxol (generic name paclitaxel) is derived from the bark of the Pacific yew tree (Taxus brevifolia), and currently considered one of the most important anticancer agents.[22] The use of taxol was approved for the treatment of advanced ovarian cancer and metastatic breast cancer. It showed impressive activity for the treatment of different types of cancers such as breast, lung, head and neck, prostate, ovarian and cervical cancers, and Kaposi's sarcoma
  • Podophyllotoxin: isolated from the roots of the North American Podophyllum peltatum Linnaeus, it has become an important pharmaceutical compound from which anticancer, anti-arthritis, and antiwart compounds are derived[23]
  • Betulinic acid (BA): It is isolated from many plant species including Betula alba which has antiretroviral, antimalarial, anti-inflammatory, and anticancer properties. Extensive evidence indicates that BA possesses a broader spectrum of activity against a great number of cancer cell types.[24] Initially, BA was reported to be the growth inhibitor of human melanoma in athymic mice[25]
  • Camptothecin: It is isolated from the Chinese ornamental tree Camptotheca acuminata, also known as the “tree of joy” or “tree of love.” It shows anticancer activity mainly for solid tumors (e.g., colon and pancreatic cancers).[26]


Vaccinations

  • Hepatitis B virus vaccine is currently used for the prevention of hepatocellular carcinoma[27]
  • Human papillomavirus vaccine: vaccine conjugated with amorphous aluminum salts have both shown to be highly effective and may reduce the burden of HPV-associated HNSCC[28]
  • Adenovirus Onyx-15 vaccine: Intraepithelial injection of the recombinant human adenovirus P53, 0.5 mL for 15 days, was effective in dysplastic oral leukoplakia after 24 months of follow-up[29]
  • Bacille Calmette–Guérin vaccine: Its immunotherapy was found to be effective against HNSCC through increase in the CD4+ and CD8+ lymphocyte count with an elevation in the levels of antitumor properties.[30]


Dietary supplements

  • Vitamin A: Retinoic acid (Vitamin A): Carotene and animal products such as meat, milk, and eggs are the sources of retinoic acid. Vitamin A (retinyl palmitate) is a lipid-soluble micronutrient, which acts during the promotion and progression stages of carcinogenesis, causes cell cycle arrest in the G1 phase, and allows repair of genomic damage caused by carcinogens. It also acts as an immune modulator and an inducer of apoptosis.[31],[32] The teratogenic action of retinoids has been the most serious adverse effect[33]
  • Vitamin C: L-ascorbic acid (L-AA) is found in citrus fruits such as kiwi, strawberries, papaya, and mango. The current recommended dietary allowance for ascorbic acid ranges between 100 and 120 mg/per day for adults. Daily intake of nearly 140 mg/day in case of smokers may typically reduce L-AA concentration in serum leukocytes. L-AA has a property of reacting with the superoxide produced as a result of the cells' normal metabolic processes; this inactivation of superoxide inhibits the formation of nitrosamines during protein digestion and helps avoid damage to the DNA and cellular proteins. Vitamin C is the most prevalent antioxidant component of fruits and vegetables. It protects cells from oxidative DNA damage, thereby blocking the initiation of carcinogenesis[34]
  • Vitamin E: α-tocoferol (Vitamin E) is the most common and most active form of Vitamin E. It is found in plant oil, margarine, green leaves, corn oil, peanuts, vegetable oils, fruits, and vegetables, consumed through diet. The recommended daily limit rates are 10 mg/day for adult men and 8 mg/day for adult women. α-tocoferol is an effective antioxidant at high levels of oxygen, protecting cellular membranes from lipidic peroxidation[35]


    • In addition to its antioxidant mechanism, it may act as an anti-inflammatory agent and as an inhibitor of cancer cell proliferation and growth, apoptosis, and angiogenesis.[36] Combination of Vitamin E with lycopene and selenium (Se) with different formulations and dosages has been found to be an effective management strategy for oral premalignant lesions. This combination may also reduce the incidence of second primary cancers, with yellowing of the skin as a side effect[37]


  • Vitamin B9: Folic acid is a water-soluble vitamin that is distributed widely in green leafy vegetables, beans, whole grains, citrus fruits, and animal products. A study by Mesolella et al.[38] has stated that oral dosage of folic acid 15 mg every 8 h for 6 months is effective for 80% clinical improvement in mild and moderate laryngeal dysplasia and 58% with clinically evident regression of the laryngeal leukoplakia
  • Zinc: It is an essential mineral that helps regulate key cellular functions, such as response to oxidative stress, DNA damage repair, cell cycle progression, and apoptosis. A case series by Chaitanya et al.,[39] Mehdipour et al.,[40] and Thomas et al.[41] suggested that different formulations of zinc with different dosages were effective in reducing the severity of lesions in subacute and chronic eczema, oral lichen planus, and psoriasis.
  • Selenium (Se): It is an essential nutritional element. Many whole grains and dairy products, including milk and yogurt, are good sources of Se. Pork, beef, chicken, fish, shellfish, and eggs contain high amounts of Se. Se is a trace element having its own codon in the mRNA, selenocysteine (SeCys), which specifies its insertion into the selenoproteins, protects tissues and membranes from oxidative stress, and controls the cell redox status. It inhibits the initiation and promotion phases of carcinogenesis. Combination of Se with Vitamin A, C, and E is effective in managing ulcerative lesions of oral lichen planus.[42]
  • Curcumin: Curcumin is the active component of turmeric extracted from the dried rhizome of Curcuma longa. A Phase IIB trial has suggested that oral dosage of curcumin 3.6 g twice daily for 6 months is well tolerated and demonstrates significant and durable clinical response for 6 months in oral leukoplakia.[43] Another trial has suggested that curcumin 400 mg lozenges for 3 months and oral curcumin 500 mg with topical application of turmeric oil 12 drops (600 mg) for 6 months were effective in oral submucous fibrosis through its antioxidant and anti-inflammatory properties, which enhance the neoangiogenic and antifibrotic potential in oral submucous fibrosis.[44] Curcumin has antitumor activity in the oral cavity, which can also inhibit cell growth and induce apoptosis in oral cancer cells. It has been shown to exhibit therapeutic potential against a variety of different cancers including leukemia and lymphoma, gastrointestinal cancers, genitourinary cancers, breast cancer, ovarian cancer, head-and-neck squamous cell carcinoma, lung cancer, melanoma, neurological cancers, and sarcoma[45]
  • Green tea polyphenols: Tea is obtained from the dried leaves of the plant Camellia sinensis. Oral administration of green tea extracts 350 mg thrice daily for 12 weeks showed that high-dose green tea extract (750 and 1000 mg/m2) had a significant clinical and histological outcome in oral premalignant lesions. It is the most biologically active catechin – are likely a result of inhibition of tumor initiation and promotion, induction of apoptosis, and inhibition of cell replication rates, thus retarding the growth and development of neoplasms[46]
  • Beta-carotene: It is a Vitamin A precursor commonly found in dark green, orange, or yellowish fruits and vegetables, such as spinach, sweet potato, carrots, papaya, mango, and oranges. A randomized controlled trial suggested that oral dosage of beta-carotene 30–90 mg/day for 6 months showed a complete clinical response of 8.3% and partial clinical response of 62.5% in oral leukoplakia,[47] whereas the dosage of 15 mg/day four times a day for 4 months reduced the multinucleated exfoliated cell frequency in atrophic and erosive oral lichen planus.[48] Zheng et al. conducted studies on nutrient levels in the blood and suggested that deficiencies in carotenoids and Vitamin E are associated with increased risk for oral and pharyngeal cancers[49]
  • Lycopene: It is a bright red carotene, carotenoid pigment and a phytochemical found in tomatoes and other red fruits and vegetables, such as red carrots, watermelons, and papayas. Lycopene has been hypothesized to prevent carcinogenesis and atherogenesis by protecting critical cellular biomolecules, including lipids, lipoproteins, proteins, and DNA. According to various studies, lycopene when given in a dosage of 4–8 mg/day orally for 3 months showed reduction in hyperkeratosis in 80% of cases, and complete remission of the lesion was noted in 55% in the oral leukoplakia[50]
  • Resveratrol: It is a component of grape skin, red wine, berries, peanuts, and many other plants. It induces differentiation and apoptosis in a multitude of cancer cell lines, such as leukemia, hepatoma, neuroblastoma, prostate cancer, colon cancer, gastric cancer, pancreatic cancer, esophageal tumorigenesis, breast cancer cells, and human melanoma cells[51]
  • Omega-3 fatty acids: Omega-3 fatty acids are found in foods, such as fish and flaxseed, and in dietary supplements, such as fish oil, and they influence multiple targets implicated in various stages of cancer development, including cell proliferation, cell survival, angiogenesis, inflammation, and metastasis against various cancers[52]
  • Neem: Gallic acid, catechin, and epicatechin are phytochemicals related to oral cancer, which have a carcinogen-detoxifying enzyme, glutathione. Catechin can inhibit the production of metalloproteases, reducing the invasion and migration and inducing the apoptosis of cancer cells. It has anti-inflammatory potential by the suppressive activation of NF-κB, which induces the apoptosis of cancer cells[53]
  • Mushrooms such as shiitake, maitake, reishi, and some Agaricus species fight against cancer and improve the immune system because of the presence of certain glucans and polysaccharide peptides (proteoglycans)[54]
  • Spirulina: Spirulina grows naturally in mineral-rich alkaline lakes which can be found in every continent. It is a healthy food containing antioxidants, phytonutrients, essential fatty acids, probiotics, and nutraceuticals. Spirulina is an excellent source of protein, beta-carotene, gamma linolenic acid, B-vitamins, minerals, chlorophyll, sulfolipids, glycolipids, superoxide dismutase, phycocyanin, and enzymes. It is cultivated, processed, and marketed globally for its wealthy dietary products and has been extensively used in health foods, pharmaceutical, and specialty feed sectors. The nutrients present in Spirulina boost the immune system and enhance the body's ability to generate new blood cells to prevent disease and cancer.[55]



  Discussion Top


Chemopreventive agents can operate at different levels of carcinogenesis. In the initiation phase, they block or delay the process of carcinogen activation. In the promotion phase, the initiated cells are actively converted into preneoplastic cells, which are more prone to malignancy, and the agents used are ideally described as suppressing agents.[56]

These chemopreventive agents also present the anti-initiation activity through inhibition of metabolic activation of carcinogens. Therefore, their action at the root level could be used for eliminating the chance of occurrence of any premalignancies. An ideal chemopreventive agent must possess the characteristics of negligible or no toxicity, high efficacy at multiple sites, and availability of oral consumption with a wide range of therapeutic actions, low cost, and human acceptance. It should have excellent bioavailability at the targeted site.

Dietary supplements such as fruits and vegetables are rich in many of the chemotherapeutic agents such as Vitamins A, C, and E; spirulina, Se, green tea (EGCG), neem, tomatoes (lycopene), turmeric (curcumin), and some medicinal mushrooms.

Important habits to be practiced to prevent oral cancer: eat more fresh fruits and vegetables, improve oral hygiene, choose cancer-fighting foods in your diet, see your dentist or dental hygienist regularly, conduct a self-exam at least once a month, and exercise regularly. The mechanism by which these dietary regimens work to prevent oral cancer is by detoxification of enzymes or other metabolic genes. Quit smoking, avoid drinking excess alcohol, decrease the use of betel quid/pan, stop using tobacco in the quid, and avoid excessive sun exposure.[15]


  Conclusion Top


An ideal chemopreventive agent mediates the beginning stage of carcinogenesis to remove premalignant cells so that malignancy can be prevented. They do so by impeding or interfering the promotion or progression of premalignant or malignant cells by modulating cell proliferation or differentiation. Furthermore, they could also be used in blocking the initiation of premalignant pathologies. More studies should be directed toward such preventive strategies in individuals with an elevated risk of cancer development for more accurate prognosis.

Chemoprevention provides an opportunity in achieving this aim, by arresting and reversing neoplastic progression before invasive carcinoma develops.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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