Home | About IJMPO | Editorial board | Search | Ahead of print | Current Issue | Archives | Instructions | Subscribe | Advertise | Contact us |  Login 
Indian Journal of Medical and Paediatric Oncology
Search Article 
Advanced search 

 Table of Contents      
Year : 2012  |  Volume : 33  |  Issue : 2  |  Page : 71-79  

Arecanut as an emerging etiology of oral cancers in India

1 Consultant Maxillofacial Surgeon, Shalby Hospitals, Ahmedabad, India
2 Department of Surgery, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Head & Neck Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication14-Aug-2012

Correspondence Address:
Gunjan Shah
6, Tatsat Society, Behind C. N. Vidyalaya, Ambavadi, Ahmedabad 380 015, Gujarat
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0971-5851.99726

Rights and Permissions

Arecanut (AN) usage is widespread in Asian countries, especially India and Taiwan. The incidence of oral cancer is increasing day by day, but there is no exponential increase with tobacco usage. Especially in the country like Taiwan where betel quid mostly do not contain tobacco, AN can be correlated with the increased incidence of cancer. There are different studies in the literature about AN and oral cancer but none of them have concluded with the definite pathway for carcinogenesis. The present paper includes reviews of the literature for AN and oral cancer and summarizes the possible mechanisms associated with AN-induced carcinogenesis; and we have also tried to propose pathway of carcinogenesis.

Keywords: Arecanut, Asian countries, betel quid, carcinogenesis, oral cancer

How to cite this article:
Shah G, Chaturvedi P, Vaishampayan S. Arecanut as an emerging etiology of oral cancers in India. Indian J Med Paediatr Oncol 2012;33:71-9

How to cite this URL:
Shah G, Chaturvedi P, Vaishampayan S. Arecanut as an emerging etiology of oral cancers in India. Indian J Med Paediatr Oncol [serial online] 2012 [cited 2020 Jul 5];33:71-9. Available from: http://www.ijmpo.org/text.asp?2012/33/2/71/99726

  Introduction Top

Burden of oral malignant disease and premature death related to that is the burning issue in Asian countries. The association of betel quid with cancer could be concluded almost 100 years back; from the pre-Christian era, the records could be traced and was used as medical as well as psychosomatic substance as a breath refresher, digestive agent, worm expellant, aphrodisiac, and to maintain stamina. [1],[2] In the recent era, the usage of betel quid was reintroduced almost 400 years when it was introduced from European traders. [1] The increased incidence of cancer in the recent population can be due to the change in the method of usage, i.e., keeping at particular site rather than rapid chewing and swallowing of all the contents, thereby decreasing direct contact time with the oral mucosa. The use of betel quid has become culturally accepted practice in India, which has now become a public health problem. [3],[4]

The concept about role of arecanut (AN) as etiology for oral cancer emerged from Taiwan, where 10% of the population is pure AN chewer and 80% of the preparations do not contain tobacco; on the other side, most of the quid preparation in India contains tobacco. [4]

Tobacco has become a social nuisance now; so, most of the people have switched over to other nontobacco-containing products such as pan-masala that contain AN and lime with other condiments. The other side of the coin is that most of the people including medical professionals are unaware about the side effects of AN: Carcinogenicity and addiction. There are a few in vitro and in vivo studies as well as review articles in the literature stating the role of AN as a carcinogen, but exact carcinogenic pathway has not been clarified yet. [1] This paper intends to present the role of AN as carcinogen, suggest a carcinogenic pathway, and reviews the literature.

AN industry counts almost 300 crore every year; there are 200 billion users; it is openly sold and advertised all over public places without warning. [5] State of California-Environmental protection agency, Office of environmental health hazard assessment-Safe drinking water and toxic enforcement act of 1986 has considered AN as carcinogenic agent in February, 2006. [6] The incidence of oral submucous fibrosis (OSF) from betel nut rages form 0.9 to 4.7% in China, whereas in the India, that is almost up to 0.4 to 10%; [7] and malignant transformation rate of 7.6% in an Indian cohort over a period of 17 years; while in Pakistan, the rate is quite more. [8],[9]

In 1969, the International Agency for Research on Cancer (IARC) initiated a program on the evaluation of the carcinogenic risk of chemicals to human beings, involving the production of critically evaluated monographs on individual chemicals. With Supplement 6 (IARC, 1987a), the title of the series was modified from IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans to IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. The criteria established in 1971 to evaluate carcinogenic risk to human beings were adopted by the working groups whose deliberations resulted in the first 16 volumes of the IARC Monographs series. Those criteria were subsequently updated by further ad hoc working groups. [10],[11]

In 2003, IARC has considered AN as group 1 human carcinogen. The 2004 monograph includes evaluation of working groups, working procedures, exposure data, etc. The monographs include composition of different substances, industrial packages, geographic region-wise consumption, regulation and legislation, studies of cancer in human and experimental models, physiologic and toxic effects. [10],[11]

  What is Arecanut? Top

AN (areca catechu--an endosperm (nut/fruit) from tropical tree Areca catechu Linnaeus) is the fourth commonly used psychoactive substance chewed as an aid to digestion and as stimulant, either used alone or added with different tobacco or nontobacco substances to make different combinations. AN is a part of betel quid commonly consumed in Asian countries. [12] "betel nut" is a wrong terminology commonly used for AN; betel tree do not contain fruits but contain only leaves--betel leaves.

AN is known to produce mutagenic and genotoxic effects on tissues of body which may lead to various neoplastic and preneoplastic lesions. [7],[11] Commission on cancer (COC) has first considered carcinogenesis of AN in 1993-1994. [13] The target cells of AN are oral fibroblast/myofibroblasts and keratinocytes. [14]

Different types of AN-containing commercially available preparations are available; most of the quids available in India contain tobacco [Table 1]. AN may be used as [11],[12] unripe/ripe, whole/sliced, raw/roasted/sun dried, boiled/soaked in water, or fermented (under mud). Depending upon the type of curing, there are many types of AN. Marked reductions in the chemical constituents (carcinogens) were observed when the AN was subjected to soaking and boiling. [13] Boiled nut is due to change in arecanut extract (ANE) composition. [15] In contrast, van Wyk stated that boiled nut contained highest amount of ANE [16] (contents of Arecanut-[Table 2]).
Table 1: Composition of the different types of chewing substances[10],[11]

Click here to view
Table 2: Contents of arecanut[11],[12]

Click here to view

  Epidemiologic Studies Top

AN is consumed widespread in Asia. In countries like India, Pakistan, Bangladesh, Sri Lanka, tobacco is often added, and consumption is higher in women. However, in countries like Taiwan (China) (10% of the population is AN users), Hainan (southern China), and Papua New Guinea (80% of the population is AN users), tobacco is never added. Studies done by Dayal 1978 (1.5% in Ahmedabad mill workers), Gupta 1996 (0.5% in Mumbai), and Daftary 1980 (0.7% in Ernaculam) have reported very less percentage of pure AN chewers. However, on contrast, studies by Chakraborty 1990 (11.4% West Bengal) and Shah 2002 (28.9% Pakistan primary school children) have shown higher rate of consumption. [11]

On the other hand, Taiwanese studies have shown higher AN consumption rate of almost 50%: Tang 1997 (China Hunan 20.3% AN, 15.1% AN with smoking), Ko 1992 (Taiwan 42.1% AN), Yang et al. 2001 (Taiwan 47.8% chewing only, total 69.5%). [11]

There are so many Indian studies reported in the literature but most of them have studied betel-quid that mostly contain tobacco in Indian scenario. However, some international studies have studied pure AN and there are two meta-analysis. The AN in quid along with tobacco may play synergistic role for carcinogenesis [Table 3].
Table 3: Epidemiologic studies

Click here to view

  Psychoactive Properties Top

AN is the fourth commonly used psychoactive substance used worldwide, after tobacco, alcohol, and caffeine-containing beverages. AN quid chewing has claimed to produce a sense of well being, euphoria, warm sensations of the body, sweating, salivation, palpitation and heightened alertness, tolerance to hunger, and increased capacity and stamina to work. All these neurological effects suggest that chewing AN quid influences central and autonomic nervous system at various levels. [12] These effects of AN are habit and dose related and is stronger for fresh or occasional chewers than in habitual chewers. Different people have reported different studies regarding this property. [11]

AN psychosis was originally described about 25 years ago in Papua New Guineans by Burton-Bradley (1977). He described how traditional healers challenged victims with so-called betel nut to induce insanity as a part of their diagnostic strategy [11],[36] [Table 4].
Table 4: Psychoactive properties

Click here to view

  Pathogenesis of Carcinoma Top

Emerging evidence indicates that sustained stress exposure induces epigenetic reprogramming of some mammalian cells, thereby increasing mutation rate to accelerate adaptation to stressful environments. [47] ANE has been shown to be mutagenic and genotoxic in a variety of short-term assay systems.

Oral carcinogenesis is a complex, multi-step process that includes initiation, promotion, and progression and is thought to be resulting from the progressive accumulation of genetic lesions after long-term betel-quid (BQ) exposure. [46] Interaction between presumed carcinogens and cellular macromolecules such as DNA, proteins, and lipids is the most important and decisive event of the chemical carcinogenesis. [48],[49] Toxicity studies relating to AN-containing polyphenols and tannins are not conclusive, with both carcinogenic and anticarcinogenic effects being reported. [46] Thus, the target organs for tumorigenesis by AN extract and AN polyphenols may be different. [46]

  Carcinogens in Arecanut Top

The contents that are proven as carcinogens are tannins, some of the polyphenols: Safrole, hydroxychavicol, and catechins, and most of the alkaloids. Some constituents of betel leaf are known to have antimutagenic effects; hydroxychavicol, eugenol.

When the alkaloids are compared on a weight basis with the extract, no single agent has detectable effects on the cells at concentrations of the extract that cause decrease colony survival and DNA single-strand breaks. Therefore, additive or synergistic effects could be considered among the alkaloid. [51]


Lime is commonly consumed compound along with AN. In the presence of lime (calcium hydroxide), arecoline and guvacoline are hydrolyzed to arecaidine and guvacine. Bacterial enzyme nitrite reductase from denitrifying (Pseudomonas) and non-denitrifying (E. coli, Proteus) bacteria aids in catalysis of nitrosation of secondary amines; [52] and poor oral hygiene also play a role. Thiocyanate in the oral cavity, catechu, and lime also act as a catalyst at pH 9.5. Enhanced by Fe 2+ , Fe 3+ , Cu 2+ , and inhibited by Mn 2+ . [9] The formation occurs through autoxidation, redox cycling via quinone/semiquinone radical, and iron-catalyzed Haber-Weiss and Fenton reactions. [9]

Arecoline is parasympathomimetic while arecaidine lacks that action. Arecaidine is more potent, cytotoxic, and mutagenic and is tumor promoter. In vitro, this action is prevented by antioxidants such as Glutathione, N- Acetyl L-Cysteine. Arecoline is de-esterified in liver while other compounds are excreted in urine. The metabolic interconversion of arecoline and arecoline 1-oxide is possible. [53] ANE increase salivary flow and decrease pH that may render tissue to more cytotoxic effects. [1]

Nitrosation of arecoline leads to four N-Nitroso compounds: N-Nitrosoguvacoline (NGCO), N-Nitroso guvacine, 3 (Methylnitrosamino) propionitrile (MNPN), 3 (Methylnitrosamino) propionaldehyde. [4],[11],[13]

These nitroso compounds have been detected in the saliva of AN chewers and are thought to be the culprit of carcinogenesis. Among all these compounds, NGCO is the most significant one. In in vitro studies, MNPN has also shown carcinogenicity. [11],[13]


Polyphenols are likely to contribute to the marked toxicity of the extract. Safrole is also a major component extracted from betel-quid preparation in Taiwan. Its metabolites found in the oral cavity are eugenol and dihydroxychavicol. That had been extendedly studied showing DNA adducts formation in vitro by 32P-postlabeling assay, regarded as a genotoxic carcinogen in the rat liver. Eugenol, a major polyphenol of betel-quid, is cytotoxic to human buccal mucosal fibroblasts by decreasing cellular ATP level and lipid peroxidation. A recent report further suggests role of safrole in oral carcinogenesis, by demonstrating safrole forms, safrole-DNA adducts in human oral tissue following betel-quid chewing. [54]

In contrast, according to some studies, hydroxychavicol and eugenol extracted from betel leaf have antimutagenic effects against dimethylbenzanthracene-induced mutagenesis. [55],[56]

  Mode of Action Top

Host defense modulation glutathione

Glutathione is tripeptide involved in detoxification of toxic electrophilic xenobiotics, is reducing agent and antioxidant, and is responsible for cell cycle and thermoregulation. [15]

ANE and polyphenols increase glutathione; while arecoline decrease glutathione; and both decrease protein-sulfhydryl (SH) content. Protein-SH is important for cell division and differentiation and many carcinogens inhibit protein-SH as part of carcinogenesis. [57] ANE decreases GST (glutathione S transferase) and acid soluble sulfhydryl (-SH) levels; while, increases cytochrome b 5 and P-450 levels in mice. [58] Thus, they impair host defense.

ANE and arecoline increases PgE2, IL-6, TNF-β in CD4 and CD8 cells, thereby causing impaired T cell activation. In keratinoblasts (KB) cells, these causes COX2 expression and inflammation that leads to decreased cell growth and cell cycle arrest and apoptosis [Figure 1]. [59]
Figure 1: Molecular events

Click here to view

Inflammatory mediators prostaglandins

ANE activate mitogen-activated protein kinase superfamily (ERK, c-JNK, p38) and transcription factor NF-κB in oral keratinocytes that are important signaling elements. ANE did not act on EGF receptor signaling system but blockage of NF-κB activation leads to ANE-modulated COX-2 upregulation. [60] But COX-2 mRNA and protein expression upregulation are reversible and can be inhibited by indomethacin and aspirin. Thus, it is not the main pathway. [61] Arecoline induces COX-2 expression in sperm cells in dose-dependent manner and decrease motility. [62]

  Reactive Oxygen Species Top

Various AN constituents may generate reactive oxygen species (ROS) (O 2 , H 2 O 2 , OH) in the presence of lime but catechin fraction is the most active producer. Fe2+ had additive effect, while Mg2+ has marked inhibitory effect. [63] ROS are responsible for oxidative DNA base tissue damage. ROS can be detected by presence of o- and m-tyrosine in saliva of chewer. [64] ANE induces micronuclei and cytokinesis failure in ovary cells in vitro. These changes are associated with increased intracellular H 2 O 2 levels and actin filament disorganization. [65]

In order to provide a defense mechanism against the attack of ROS, cells may exert nonenzymatic and enzymatic systems incorporating agents such as Gluthione S transferase (GSH), catalase, superoxide dismutase (SOD), and glutathione peroxidase, in order to prevent or minimize the toxic damage potentially elicited by ROS. [66],[67] ROS acts by (1) Directly gene mutations, (2) Attack salivary proteins and oral mucosa--structural changes--penetration of various objects, (3) Inflammatory cell infiltration--more ROS--mutation of adjacent cells. [46]

ANE-induced unscheduled DNA synthesis (UDS) in gingival keratinocytes may be inhibited by vitamin C, glutathione, desferoxamine (iron chelator and free radical scavenger); while, banthocuproine (copper chelator), 1,10-phenanthroline (lipid permeable iron chelator), and specific reactive oxygen species scavengers such as dimethyl-sulfoxide, mannitol, dimethylthiourea, pyruvate, catalase, and SOD lacked these preventive effects. Higher concentrations of H 2 O 2 inhibited the basal levels of UDS. Thus, it can be stated that these effects are associated with free radical reaction. [68]

However, the extracellular addition of GSH and cysteine has been shown to prevent the arecoline cytotoxicity to cultured OMF in vitro, although SOD and catalase lacked similar preventive effects. This indicates that the cytotoxicity of arecoline to cultured OMF is not mediated by the extracellular production of superoxide radicals and H 2 O 2 . [69]

Cell damage

Salivary AN-specific carcinogen 3NPA is known to form DNA protein cross-links and DNA single-strand breaks. [51] Different concentrations of extracts of AN induced dose-dependent UDS in Hep 2 cells. Aqueous and acetic acid extract induce relatively more UDS. [70] Arecoline lowers poly ADP ribosylation in most cellular proteins in Swiss mice. These changes may be the earlier events for initiation of carcinogenesis. [71] Arecoline induced cyclin β1, wee1, phosphorylated CDC 2 protein, and declined p21 expression in KB epithelial cells in gingival Gingival keratinocytes causes the reverse action and ultimately leads to arrest of late S, G2/M cycle. Thus, differential regulation of S and/or G2/M cell cycle-related proteins in the GK and KB cells play a crucial role in different stages of AN-mediated carcinogenesis. [72] ANE is known to cause upregulation of Asb6, a coupling protein to the adapter protein with Pleckstrin homology and Src homology 2 adapter protein, which is involved in insulin signaling for glucose transportation which can be used as prognostic marker. [73] Amount of substance needed for an event is shown in the [Table 5].
Table 5: Amount of substance needed for an event

Click here to view

  Genes/Biomarkers Top

DNA repair machineries play a pivotal role in maintaining genome integrity. Deregulation of DNA repair can result in genomic instability, which is a hallmark of cancer cells. [74]

p53 plays important role in cellular response to stress and is tumor suppressor gene, is the most frequent target (90% involve missense mutation in one allele) for genetic alterations in cancer, and involves in more than 50% of cancers. In Taiwanese, oral cancers infrequent p53 mutations have been reported and 80% of the etiology involves betel-quid which do not contain tobacco in Taiwanese formulations. [75] Some reports from India have also shown infrequent p53 mutation. [76] There is an alternative mechanism of p53 inactivation besides mutations. The mechanism may be either inactivation by abrogating specific DNA binding resulting in p53 sequestering or other genes related to oral cancer (p16/pRb pathway, p21ras, cyclin D1, CD44v7-8, c-myc, N-myc, and Ki-ras). [76]

The role of tissue growth factor (TGF)-β in epithelial malignancy is complex, but it is becoming clear that in the early stages of carcinogenesis, the protein acts as a potent tumor suppressor, while later, TGF-β can function to advance tumor progression. [77] The observed methylation of the p16/MTS1 promoter regions for 54% of tongue squamous-cell carcinoma specimens obtained from BQ-chewers has recently been reported. [78]

ANE induces c-jun proto-oncogene mRNA levels and the effect is independent of glutathione. This may be the mechanism of carcinogenesis. [79],[47] Patients with that have poor prognosis. Liu et al. demonstrated presence of safrole DNA adducts in peripheral blood lymphocytes. That can be traced to polymorphism of the CYP2E1 gene, alone and in combination with the GST M1 and GST T1-deletion polymorphisms. Thus, CYP2E1 plays important role for adduct formation. [80]

ANE has shown mutagenicity to S. typhi strains in in vitro studies. [9] It has also induced chromosomal aberrations, sister chromatid exchange, and micronucleated cells and decrease in sperm motility and tumor production in other organs in other in vitro studies. [9]

Arecoline can induce hyperphosphorylation of γ-H2AX which is a marker to examine DNA damage. Upon DNA damage, various molecular events result and ataxia telangiectasia mutated (ATM) kinase plays an important role. Arecoline induces γ-H2AX phosphorylation, triggers ATM-dependant signal pathway and G2/M cycle arrest, suppresses DNA repair, and inhibits expression and transactivation function of p53. [74]

  Submucus Fibrosis Top

Pathogenesis is centered with extracellular matrix. Different AN constituents are involved with the collagen production and degradation pathways and they increase collagen production and inhibit collagen degradation thereby causing fibrosis. [81] The reports have shown association between copper content and amount of fibrosis found in other fibrotic disorders such as Wilson's disease, biliary and Indian childhood cirrhosis; upregulation of lysyl oxidase is also seen: An enzyme associated with collagen synthesis and cross-linkage. [82] Upregulation of COX-2 and increased levels of proinflammatory cytokines and reduced levels of anti-fibrotic IFN-γ are also found. Genetic polymorphism is also found to be associated. Increased production of tissue inhibitors of matrix metalloproteinases protein is found in OSF. [83] Autoimmunity is also shown to be involved with that.

  Conclusion Top

The pathogenesis of AN carcinogenesis is a complex multistep process involving various pathways and constituents. Carcinogenesis of tobacco is well known and reported in the literature, but no single study is found that has completely supported definite carcinogenesis pathway. Different in vivo and in vitro studies have shown different pathway of carcinogenesis, but when substance inhibiting that particular pathway was used that has not completely inhibited the cellular changes caused by AN substitute. On the other hand, when effects caused by a single AN agent were blocked, even then carcinogenesis was found. So, neither single agent is responsible nor single pathway can produce carcinogenesis and oral submucus fibrosis (OSMF) is related with the carcinogenesis and definite genetic mutations are found to be present.

  References Top

1.Gupta PC. Areca nut use in India. Indian J Med Sci 2007;61:317-9.  Back to cited text no. 1
[PUBMED]  Medknow Journal  
2.Sharan RN. Association of betel nut with carcinogenesis: A review. Cancer J 1996;9:13-19.  Back to cited text no. 2
3.Bobba R, Khan Y. Cancer in India - An Overview. GOR 2003;5:93-6.  Back to cited text no. 3
4.Control of oral cancer in developing countries. A WHO meeting. Bull World Health Organ 1984;62:817-30.  Back to cited text no. 4
5.Ray CS, Gupta PC, Beyer JD. Research on tobacco in India (including betel quid and areca nut)- An annotated bibliography of research on use, health effects, economics, and control efforts August, 2003.  Back to cited text no. 5
6.State of California Environmental protection agency chemicals known to the state to cause cancer or reproductive toxicity February 3, 2006.  Back to cited text no. 6
7.Trivedy CR, Craig G, Warnakulasuriya S. The oral health consequences of chewing Arecanut. Addict Biol 2002;7:115-25.  Back to cited text no. 7
8.Murti PR, Bhonsle RB, Pindborg JJ, Daftary DK, Gupta PC, Mehta FS. Malignant transformation rate in oral submucous fibrosis over a 17-year period. Community dent. Oral Epidemiol 1985;13:340-1.  Back to cited text no. 8
9.Nair U, Bartsch H, Nair J. Alert for an epidemic of oral cancer due to use of the betel quid substitutes gutkha and pan masala: A review of agents and causative mechanisms. Mutagenesis 2004;19:251-62.  Back to cited text no. 9
10.International Agency for Research on Cancer: IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 37, Tobacco Habits other than Smoking; Betel-quid and Areca-nut Chewing; and some related Nitrosomines. Lyon: International Agency for Research on Cancer; 1984.  Back to cited text no. 10
11.International Agency for Research on Cancer: IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans Vol. 85, Betel-quid and Areca-nut Chewing and Some Areca-nut-derived Nitrosamines. Lyon: International Agency for Research on Cancer; 2003.  Back to cited text no. 11
12.Rooban T, Joshua E, Rooban A, Kumar G, Govind. Health hazards of chewing arecanut and products containing arecanut. Calicut Med J 2005;3:e3.  Back to cited text no. 12
13.COC 2008 Statement on Betel Quid, Pan Masala and Areca Nut Chewing COC/08/S2 - July 2008. Available from: http://www.iacoc.org.uk [Last accessed on 2008 July].  Back to cited text no. 13
14.Sundqvist K, Grafstrom RC. Effects of areca nut on growth, differentiation and formation of DNA damage in cultured human buccal epithelial cells. Int J Cancer 1992;52:305-10.  Back to cited text no. 14
15.Saraswathi TR, Sheeba T, Nalinkumar S, Ranganathan K. Effect of glutathione on arecanut treated normal human buccal fibroblast culture. Indian J Dent Res 2006;17:104-10.  Back to cited text no. 15
[PUBMED]  Medknow Journal  
16.Van Wyk CW, Olivier A, De Miranda CM, Van der Bijl P, Grobler-Rabie AF. Observations on the effect of areca nut extracts on oral fibroblast proliferation. J Oral Pathol Med 1994;23:145-8.  Back to cited text no. 16
17.Shanta V, Krishnamurthi S. A study of aetiological factors in oral squamous cell carcinoma. Br J Cancer 1959;13:381-8.  Back to cited text no. 17
18.Chandra A. Different habits and their relation with cancer cheek. Chittaranjan cancer hospital, Calcutta. Natl Cancer Res Centre Bull 1962;1:33-6.  Back to cited text no. 18
19.Hiramaya T. An epidemiological study of oral and pharyngeal cancer in central and south-east asia. Bull World Health Oragan 1966;34:41-69.  Back to cited text no. 19
20.Jafarey NA, Zaidi SH. Carcinoma of the oral cavity and oropharynx in Karachi. An Apraisal. Trop Doct 1976;6:63-7.  Back to cited text no. 20
21.Sankaranarayanan R, Duffy SW, Day NE, Nair MK, Padmakumary G. A case-control investigation of cancer of the oral tongue and the floor of the mouth in Southern India. Int J Cancer 1989;44:617-21.  Back to cited text no. 21
22.Sankaranarayanan R, Mathew B, Jacob BJ, Thomas G, SomanathanT, Pisani P, et al. For the Trivandrum Oral Cancer Screening Study Group. Early findings from a community-based, cluster-randomized, controlled oral cancer screening trial in Kerala, India. Cancer 200;188:664-73.  Back to cited text no. 22
23.Nandakumar A, Thimmasetty KT, Sreeramareddy NM, Venugopal TC, Rajanna, Vinutha AT, et al. A population-based case-control investigation on cancers of the oral cavity in Bangalore. India. Br J Cancer 1990;62:847-51.  Back to cited text no. 23
24.Ko YC, Huang YL, Lee CH, Chen MJ, Lin LM, Tsai CC. Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan. J Oral Pathol Med 1995;24:450-3.  Back to cited text no. 24
25.Lu CT, Yen YY, Ho CS, Ko YC, Tsai CC, Hsieh CC, et al. A case control study of oral cancer in Changhua County, Taiwan. J Oral Pathol Med 1996;25:245-8.  Back to cited text no. 25
26.Dikshit RP, Kanhere S. Tobacco habits and risk of lung, oropharyngeal and oral cavity cancer: A population based case control study in Bhopal, India. Int J Epidemiol 2000;29:609-14.  Back to cited text no. 26
27.Hashibe M, Mathew B, Kuruvilla B, Thomas G, Sankaranarayanan R, Parkin DM, et al. Chewing tobacco, alcohol and the risk of erythroplakia. Cancer Epidemiol Biomarkers Prev 2000;9:639-45.  Back to cited text no. 27
28.Merchant A, Hussain SS, Hosain M, Fikree FF, Pitiphat W, Siddiqui AR, et al. Paan without tobacco: An independent risk factor for oral cancer. Int J Cancer 2000;86:128-31.  Back to cited text no. 28
29.Balaram P, Sridhar H, Rajkumar T, Vaccarella S, Herrero R, Nandakumar A, et al. Oral cancer in southern India: Influence of smoking, drinking, paan chewing and oral hygiene. Int J Cancer 2002;98:440-5.  Back to cited text no. 29
30.Chen PC, Kuo C, Pan CC, Chou MY. Risk of oral cancer associated with human papillomavirus infection, betel quid chewing, and cigarette smoking in Taiwan- an integrated molecular and epidemiological study of 58 cases. J Oral Pathol Med 2002;31:317-22.  Back to cited text no. 30
31.Znaor A, Brennan P, Gajalaxmi V, Mathew A, Shanta V, Vargese C, et al. Independent and combined effects of tobacco smoking, chewing and alcohol drinking on the risk of oral, pharyngeal and esophageal cancers in Indian men. Int J Cancer 2003;105:681-6.  Back to cited text no. 31
32.Chitra S, Ashok L, Anand L, Srinivasan V, Jayanthi V. Risk factors for esophageal cancer in Coimbatore, southern India: A hospital-based case-control study. Indian J Gastroenterol 2004;23:19-21.  Back to cited text no. 32
33.Thomas SJ, Bain CJ, Battistutta D, Ness AR, Paissat D. Betel quid not containing tobacco and oral cancer: A report on a case-control study in Papua New Guinea and a meta-analysis of current evidence. Int J Cancer 2007;120:1318-23.  Back to cited text no. 33
34.Zhang X, Reichart PA. A review of betel quid chewing, oral cancer and precancer in Mainland China. Oral Oncol 2007;43:424-30.  Back to cited text no. 34
35.Thomas SJ, Harris R, Ness AR, Taulo J, Maclennan R, Howes N, et al. Betel quid not containing tobacco and oral leukoplakia: A report on a cross-sectional study in Papua New Guinea and a meta-analysis of current evidence. Int J Cancer 2008;123:1871-6.  Back to cited text no. 35
36.Burton-Bradley BG. Betel chewing in retrospect. P N G Med J 1978;21:236-41.  Back to cited text no. 36
37.Schneider E. Betel - A popular pleasure - giving substance in South Asia. Pharm Uns Zeit 1986;15:161-6.  Back to cited text no. 37
38.Norton SA. Betel: Consumption and consequences. J Am Acad Dermatol 1998;38:81-8.  Back to cited text no. 38
39.Chu NS. Effects of betel chewing on the central and autonomic nervous systems. J Biomed Sci 2001;8:229-36.  Back to cited text no. 39
40.Chu NS. Neurological aspects of areca and betel chewing. Addict Biol 2002;7:111-4.  Back to cited text no. 40
41.Cawte J. Psychoactive substances in the South seas: Betel, kava, and pituri. Aust N Z J Psychiatry 1985;19:83-7.  Back to cited text no. 41
42.Pickwell SM, Schimelpfening S, Palinkas LA. 'Betelmania'. Betel quid chewing by Cambodian women in the United States and its potential health effects. West J Med 1994;160:326-30.  Back to cited text no. 42
43.Talonu NT. Observation on betel-nut use, habituation, addiction and carcinogenesis in Papua New Guineans. P N G Med J 1989;32:195-7.  Back to cited text no. 43
44.Winstock AR, Trivedy CR, Warnakulasuriya KA, Peters TJ. A dependency syndrome related to areca nut use: Some medical and psychological aspects among areca nut users in the Gujarat community in the UK. Addict Biol 2000;5:173-9.  Back to cited text no. 44
45.Kuruppuarachchi KA, Williams SS. Betel use and schizophrenia. Br J Psychiatry 2003;182:455.  Back to cited text no. 45
46.Jeng JH, Chang MC, Hahn LJ. Role of areca nut in betel quid-associated chemical carcinogenesis: Current awareness and future perspectives. Oral Oncol 2001;37:477-92.  Back to cited text no. 46
47.Kuo R, Lin C, Kuo MY. Prognostic Role of c-Jun Activation in Patients with Areca Quid Chewing-related Oral Squamous Cell Carcinomas in Taiwan. J Formos Med Assoc 2006;105:229-34.  Back to cited text no. 47
48.Cohen SM, Ellwein LB. Genetic errors, cell proliferation and carcinogenesis. Cancer Res 1991;51:6493-5.  Back to cited text no. 48
49.Hursting SD, Slaga TJ, Fischer SM, DiGiovanni J, Phang JM. Mechanism-based cancer prevention approaches: Targets, examples and the use of transgenic mice. J Natl Cancer Inst 1999;91:215-25.  Back to cited text no. 49
50.Jeng JH, Kuo ML, Hahn LJ, Kuo MY. Genotoxic and non-genotoxic effects of betel quid ingredients on oral mucosal fibroblasts in vitro. J Dent Res 1994;73:1043-9.  Back to cited text no. 50
51.Sundqvist K, Grafstrom RC. Effects of areca nut on growth, differentiation and formation of DNA damage in cultured human buccal epithelial cells. Int J Cancer 1992;52:305-10.  Back to cited text no. 51
52.Calmels S, Ohshima H, Henry Y, Bartsch H. Characterization of bacterial cytochrome cdt-nitrite reductase as One enzyme responsible for catalysis of nitrosation of secondary amines. Carcinogenesis 1996;17:533-6.  Back to cited text no. 52
53.Nery R. The metabolic interconversion of arecoline and arecoline 1-oxide in the rat. Biochem J 1971;122:503-8.  Back to cited text no. 53
54.Jeng JH, Hahn LJ, Lu FJ, Wang YJ, Kuo MY. Eugenol triggers different pathobiological effects on human oral mucosal fibroblasts. J Dent Res 1994;73:1050-5.  Back to cited text no. 54
55.Amonkar AJ, Nagabhushan M, D'Souza AV, Bhide SV. Hydroxychavicol: A new phenolic antimutagen from betel leaf. Food Chem Toxicol 1986;24:1321-4.  Back to cited text no. 55
56.Amonkar AJ, Padma PR, Bhide SV. Protective effect of hydroxychavicol, a phenolic component of betel leaf, against the tobacco-specific carcinogens. Mutat Res 1989;210:249-53.  Back to cited text no. 56
57.Shivapurkar NM, Bhide SV. Effect of betel nut constituents on Sulfhydryl metabolism. Ind J Pharmac 1978;10:257-64.  Back to cited text no. 57
58.Singh A, Rao AR. Effect of arecanut on the black mustard (Brassica niger, L.)-modulated detoxication enzymes and sulfhydryl content in the liver of mice. Cancer Lett 1993;72:45-51.  Back to cited text no. 58
59.Jeng JH, Wang YJ, Chiang BL, Lee PH, Chan CP, Ho YS, et al. Roles of keratinocyte inflammation in oral cancer regulating the prostaglandin E 2 , interleukin-6 and TNF-B1 production of oral epithelial cells by areca nut extract and arecoline . Carcinogenesis 2003;24:1301-15.  Back to cited text no. 59
60.Lin SC, Lu SY, Lee SY, Lin CY, Chen CH, Chang KW. Areca (betel) nut extract activates mitogen-activated protein kinases and NF-kappab in oral keratinocytes . Int J Cancer 2005;116:526-35.  Back to cited text no. 60
61.Jeng JH, Ho YS, Chan CP. Areca nut extract up-regulates prostaglandin production, cyclooxygenase-2 mrna and protein expression of human oral keratinocytes. Carcinogenesis 2000;21:1365-70.  Back to cited text no. 61
62.Er TK, Tsai EM, Tsai LY, Ko YC, Lee JN. In vitro effects of arecoline on sperm motility and cyclooxygenase-2 expression. J Toxicol Sci 2006;31:75-82.  Back to cited text no. 62
63.Nair UJ, Obe G, Friesen M, Goldberg MT, Bartsch H. Role of lime in the generation of reactive oxygen species from betel-quid ingredients. Environ Health Perspect 1992;98:203-5.  Back to cited text no. 63
64.Nair UJ, Nair J, Friesen MD, Bartsch H, Ohshima H. Ortho- and meta-tyrosine formation from phenylalanine in human saliva as a marker of hydroxyl radical generation during betel quid chewing. Carcinogenesis 1995;16:1195-8.  Back to cited text no. 64
65.Lin CC, Chang MC, Chang HH, Wang TM, Tseng WY, Tai TF, et al. Areca nut-induced micronuclei and cytokinesis failure in Chinese hamster ovary cells is related to reactive oxygen species production and actin filament deregulation. Environ Mol Mutagen 2009;50:367-74.  Back to cited text no. 65
66.Kehrer JP. Free radicals as mediators of tissue injury and disease. Crit Rev Toxicol 1993;23:21-48.  Back to cited text no. 66
67.Amstad P, Cerutti P. Genetic modulation of the cellular antioxidant defense capacity. Environ Health Perspect 1990;88:77-82.  Back to cited text no. 67
68.Chang MC, Ho YS, Lee JJ, Kok SH, Hahn LJ, Jeng JH. Prevention of the areca nut extract-induced unscheduled DNA synthesis of gingival keratinocytes by vitamin C and thiol compounds. Oral Oncol 2002;38:258-65.  Back to cited text no. 68
69.Jeng JH, Kuo ML, Hahn LJ, Kuo MY. Genotoxic and non-genotoxic effects of betel quid ingredients on oral mucosal fibroblasts in vitro. J Dent Res 1994;73:1043-9.  Back to cited text no. 69
70.Sharan RN, Wary KK. Study of unscheduled DNA synthesis following exposure of human cells to arecoline and extracts of betel nut in vitro. Mutat Res 1992;278:271-6.  Back to cited text no. 70
71.Saikia JR, Schneeweiss FH, Sharan RN. Arecoline-induced changes of poly-ADP-ribosylation of cellular proteins and its influence on chromatin. Cancer Lett 1999;139:59-65.  Back to cited text no. 71
72.Lee PH, Chang MC, Chang WH, Wang TM, Wang YJ, Hahn LJ, et al. Prolonged exposure to arecoline arrested human KB epithelial cell growth: Regulatory mechanisms of cell cycle and apoptosis. Toxicology 2006;220:81-9.  Back to cited text no. 72
73.Hung KF, Lai KC, Liu TY, Liu CJ, Lee TC, Lo JF. Asb6 upregulation by Areca nut extracts is associated with betel quid-induced oral carcinogenesis. Oral Oncol 2009;45:543-8.  Back to cited text no. 73
74.Tsai YS, Lee KW, Huang JL, Liu YS, Juo SH, Kuo WR, et al. Arecoline, a major alkaloid of areca nut, inhibits p53, represses DNA repair, and triggers DNA damage response in human epithelial cells. Toxicology 2008;249:230-7.  Back to cited text no. 74
75.Yan Huaxin. Betel nut genotoxic stress. Of p53 stability. National Science Council - research report. Project number: NSC90-2314-B-039-022. Executive Unit: China Medical University School of Dentistry. Republic of China September 22,1992.  Back to cited text no. 75
76.Kannan K, Munirajan AK, Krishnamurthy J, Bhuvarahamurthy V, Mohanprasad BK, Panishankar KH, et al. Low incidence of p53 mutations in betel quid and tobacco chewing-associated oral squamous carcinoma from India. Int J Oncol 1999;15:1133-6.  Back to cited text no. 76
77.Prime SS, Davies M, Pring M, Paterson IC. The role of TGF-beta in epithelial malignancy and its relevance to the pathogenesis of oral cancer (part II). Crit Rev Oral Biol Med 2004;15:337-47.  Back to cited text no. 77
78.Lin SC, Chang KW, Chang CS, Liu TY, Tzeng YS, Yang FS, et al. Alterations of p16/MTS1 gene in squamous cell carcinomas from Taiwan. J Oral Pathol Med 2000;29:159-66.  Back to cited text no. 78
79.Ho TJ, Chiang CP, Hong CY, Kok SH, Kuo YS, Yen-Ping Kuo M. Induction of the c-jun protooncogene expression by areca nut extract and arecoline on oral mucosal fibroblasts. Oral Oncol 2000;36:432-6.  Back to cited text no. 79
80.Liu TY, Chung YT, Wang PF, Chi CW, Hsieh LL. Safrole-DNA adducts in human peripheral blood-an association with areca quid chewing and CYP2E1 polymorphisms. Mutat Res 2004;559:59-66.  Back to cited text no. 80
81.Triedy CR, Warnakulasuria KA, Hazarey VK, Tavassoli M, Sommer P, Johnson NW. The upregularion of lysyl oxidase in oral submucous fibrosis and squamous cell carcinoma. J Oral Pathol Med 1999;28:246-51.  Back to cited text no. 81
82.Tilakaratne WM, Klinikowski MF, Saku T, Peters TJ, Warnakulasuriya S. Oral submucous fibrosis: Review on aetiology and pathogenesis. Oral Oncol 2006;42:561-8.  Back to cited text no. 82
83.Shieh DH, Chiang LC, Shieh TY. Augmented mRNA expression of tissue inhibitor of metalloproteinase 1 in buccal mucousal fibroblasts by arecoline and safrole as a possible pathogenesis for oral submucous fibrosis. Oral Oncol 2003;39:728-35.  Back to cited text no. 83


  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]

This article has been cited by
1 Knowledge, Attitude and Practice of Tobacco Use and Its Impact on Oral Health Status of 12 and 15 Year-Old School Children of Chhattisgarh, India
Ram Vinod Tiwari,Jayachandra Megalamanegowdru,Anjali Gupta,Ankush Agrawal,Abhinav Parakh,Sulabh Pagaria,Abhishek Sahu
Asian Pacific Journal of Cancer Prevention. 2015; 15(23): 10129
[Pubmed] | [DOI]
2 Epidemiology of Oral Cancer in Asia in the Past Decade- An Update (2000-2012)
Sree Vidya Krishna Rao,Gloria Mejia,Kaye Roberts-Thomson,Richard Logan
Asian Pacific Journal of Cancer Prevention. 2013; 14(10): 5567
[Pubmed] | [DOI]
3 Epidemiology of oral cancer in Asia in the past decade - An update (2000-2012)
Rao, S.V.K., Mejia, G., Roberts-Thomson, K., Logan, R.
Asian Pacific Journal of Cancer Prevention. 2013; 14(10): 5567-5577


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
  What is Arecanut?
   Epidemiologic St...
   Psychoactive Pro...
   Pathogenesis of ...
   Carcinogens in A...
  Mode of Action
   Reactive Oxygen ...
  Submucus Fibrosis
   Article Figures
   Article Tables

 Article Access Statistics
    PDF Downloaded592    
    Comments [Add]    
    Cited by others 3    

Recommend this journal