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PubMed2004

The induction of prostaglandin E2 production, interleukin-6 production, cell cycle arrest, and cytotoxicity in primary oral keratinocytes and KB cancer cells by areca nut ingredients is differentially regulated by MEK/ERK activation.

There are about 200-600 million betel quid (BQ) chewers in the world. BQ chewing is one of the major risk factor of hepatocarcinoma, oropharyngeal, and esophagus cancers in Taiwan, India, and Southeast Asian countries. Thus, the precise molecular mechanisms deserve investigation. We used cultured primary keratinocytes and KB cells, RT-PCR, flow cytometry, Western blotting, and ELISA to evaluate whether alterations in early gene expression is crucial in the carcinogenic processes of BQ. We observed the induction of c-Fos mRNA expression in human gingival keratinocyte (GK) and KB carcinoma cells by areca nut (AN) extract and arecoline. A maximal increment in c-fos gene expression was shown at about 30 min after challenge. AN extract (100-800 microg/ml) and arecoline (0.1-0.8 mM) also stimulated ERK1/ERK2 phosphorylation with a maximal stimulation at 5-10 min of exposure. Pretreatment by U0126 (30 microM), a MEK inhibitor, markedly inhibited the c-Fos, cyclooxygenase-2 (COX-2), and IL-6 mRNA expression of the KB epithelial cells. In addition, U0126 and PD98059 (50 microM) also decreased AN extract- and arecoline-associated PGE2 and IL-6 production in GK and KB cells. However, U0126 by itself arrested the cells in G0/G1 phase, but was not able to prevent AN- and arecoline-induced cell death or apoptosis. In contrast, U0126 enhanced the AN-induced apoptosis of KB cells. AN ingredients thus play a significant role in the pathogenesis of oropharyngeal cancer by activation of MEK1/ERK/c-Fos pathway, which promotes keratinocyte inflammation, cell survival, and affects cell cycle progression.

Apoptosis↗
PubMed2002

Metabolic effects of the consumption of Areca catechu.

Betel nut (Areca catechu) is chewed regularly by at least 10% of the world population, imported by immigrant users wherever they settle, and is the fourth most widely used addictive substance. It is thought, by users, to soothe the digestion and to be a stimulant and its use has a major role in social situations. Specific arecal alkaloids act as competitive inhibitors of GABA receptors and have widespread effects in the body, including actions on the brain, cardiovascular system, lungs, gut and pancreas. Nitrosated derivatives of arecal alkaloids, proven carcinogens inducing tumours throughout the upper gut and foregut derivatives in animals, are also associated with increased tumour risks in man. These nitrosated compounds are also diabetogenic in CD1 mice, producing a type 2 diabetes with obesity. Increased central obesity is found in association with betel usage in man as well as increases in circulating markers of inflammatory and cardiovascular damage. The effects of chronic betel usage in man are at least as diverse as those of smoking and the habit increases the risks of ill health.

Animals↗
PubMed2002

Areca nut-abuse liability, dependence and public health.

To define a dependence syndrome may convey attention upon a public health problems hitherto relatively ignored. It may, however, stigmatize substance use, especially when western diagnostic criteria are applied to essentially culture-bound substances. However, when the pattern of use of a substance results in significant personal harm, then whether dependence exists or not is less important than developing an appropriate response, if its use is associated with significant morbidity and mortality. Such is the case with areca nut, the fourth most commonly used drug in the world after tobacco, alcohol and caffeine. In this paper I will explore its use and properties with respect to its abuse and dependence liability and consider the associated implications for public health.

Areca↗
PubMed2002

Hydroxyl radical formation and oxidative DNA damage induced by areca quid in vivo.

Chewing areca quid (AQ) has been implicated as a major risk factor for the development of oral squamous-cell carcinoma (OSCC). Recent studies have suggested that AQ-generated reactive oxygen species (ROS) is one of the contributing factors for oral carcinogenesis. However, the AQ used in Taiwan is different from that used in other countries. This study is designed to test whether ROS are generated and the consequent effects in locally prepared AQ in vivo. We measured the hydroxyl radical formation, as represented by the presence of o- and m-tyrosine in saliva from volunteers who chewed AQ containing 20 mg phenylalanine. Their saliva contained significantly higher amounts (p < .05) of o- and m-tyrosine as compared to the controls. In addition, chewing AQ containing Piper betle inflorescence generated higher amounts of m-tyrosine, but not o-tyrosine, in saliva than did chewing AQ containing betel leaf. We further tested the oxidative DNA damaging effect of the reconstituted AQ, as evidenced by the elevation of 8-hydroxy-2'-deoxyguanosine (8-OH-dG) levels, in hamster buccal pouch. Following daily painting for 14 d, the 8-OH-dG level in hamster buccal pouch is significantly elevated (p < .05) in the AQ-treated group versus the controls. These findings demonstrate that ROS, such as hydroxyl radical, are formed in the human oral cavity during AQ chewing, and chewing such prepared AQ might cause oxidative DNA damage to the surrounding tissues.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1994

Tobacco-specific N-nitrosamines and Areca-derived N-nitrosamines: chemistry, biochemistry, carcinogenicity, and relevance to humans.

Nicotine and the minor tobacco alkaloids give rise to tobacco-specific N-nitrosamines (TSNA) during tobacco processing and during smoking. Chemical-analytical studies led to the identification of seven TSNA in smokeless tobacco (< or = 25 micrograms/g) and in mainstream smoke of cigarettes (1.3 micrograms TSNA/cigarette). Indoor air polluted by tobacco smoke may contain up to 24 pg/L of TSNA. In mice, rats, and hamsters, three TSNA, N'-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), are powerful carcinogens; two TSNA are moderately active as carcinogens; and two TSNA appear not to be carcinogenic. The TSNA are procarcinogens, agents that require metabolic activation. The active forms of the carcinogenic TSNA react with cellular components, including DNA, and with hemoglobin (Hb). The Hb adducts in chewers and smokers serve as biomarkers for the uptake and metabolic activation of carcinogenic TSNA and the urinary excretion of NNAL as free alcohol and as glucuronide for the uptake of TSNA. The review presents evidence that strongly supports the concept that TSNA contribute to the increased risk for cancer of the upper digestive tract in tobacco chewers and for the increased risk of lung cancer, especially pulmonary adenocarcinoma, in smokers. The high incidence of cancer of the upper digestive tract especially among men on the Indian subcontinent has been causally associated with chewing of betel quid mixed with tobacco. In addition to the TSNA, the betel quid chewers are exposed to four N-nitrosamines that are formed during chewing from the Areca alkaloids, two of these N-nitrosamines are carcinogens. The article also reviews approaches toward the reduction of the carcinogenic potency of smokeless tobacco, betel quid-tobacco mixtures, and cigarette smoke. Although the safest way to reduce the risk for tobacco-related cancers is to refrain from chewing and smoking, modifications of smokeless tobacco and of cigarettes are indicated to lead to less toxic products. Another more recent approach for reducing the carcinogenic effect of tobacco products is the application of chemopreventive agents, primarily of micronutrients. Future aspects in tobacco carcinogenesis, especially as it relates to TSNA, are expected in the field of molecular biochemistry and in biomarker studies, with the goal of identifying those tobacco and betel quid chewers and tobacco smokers who are at especially high risk for cancer.

Animals↗
PubMed2007

Areca nut chewing and mortality in an elderly cohort study.

Compared with the well-documented association with betel-related cancer, little is known about the long-term effect of areca nut chewing on other fatal diseases. The authors' analyses were based on a population-based cohort study in Taiwan, including 4,049 participants aged 60 years or older enrolled in 1989 and 2,462 participants aged 50-66 years enrolled in 1996. Information regarding betel quid chewing and covariates was collected at baseline and was updated at subsequent interviews. Proportional hazards analysis was performed to determine the effect of chewing on all-cause and cause-specific deaths. During a mean follow-up of 9.5 years, 2,309 deaths occurred. Ever chewers were at higher risk of only total (hazard ratio = 1.19, 95% confidence interval: 1.05, 1.35) and cerebrovascular (hazard ratio = 1.66, 95% confidence interval: 1.19, 2.30) deaths. Furthermore, increased chewing-years or quid-years appeared to be associated with increased mortality risk (linear trend: p = 0.02 for total mortality and p = 0.001 for cerebrovascular mortality). The authors found that, although betel quid chewing resulted in a statistically significant increase in the risk of total and cerebrovascular deaths in the elderly population, the associations were weak and should be interpreted with caution. Further studies are needed to confirm these findings and to better understand the possible mechanisms of death.

Aged↗
PubMed2003

Roles of keratinocyte inflammation in oral cancer: regulating the prostaglandin E2, interleukin-6 and TNF-alpha production of oral epithelial cells by areca nut extract and arecoline.

Betel quid (BQ) chewing is an etiologic factor of oral cancer and submucus fibrosis (OSF). Keratinocyte inflammation is crucial for the pathogenesis of cancer and tissue fibrosis. We found that areca nut (AN) extract (100-400 micro g/ml) induced PGE2 production by KB cells by 2.34- to 23.1-fold and also TNF-alpha production by gingival keratinocytes (GK). Arecoline (0.2-1.2 mM) elevated PGE2 production by KB cells by 2.5- to 6.1-fold. AN extract (200-400 micro g/ml) also induced IL-6 production by GK (7.5- to 8.4-fold) and KB cells. In contrast, arecoline (0.1-1.2 mM) suppressed IL-6 production by GK and KB cells, with 42-81 and 41-63% inhibition, respectively. A 48 h exposure of GK to 800-1200 micro g/ml AN extract led to 37-69% cell death. Arecoline cytotoxicity to GK was noted at concentrations of 0.8-1.2 mM, which led to 28-38% cell death. AN extract (400-800 micro g/ml) induced Cox-2 and IL-6 mRNA expression and also COX-2 protein production by KB cells. IL-6 (5-100 ng/ml) suppressed GK growth by 20-33%, but enhanced oral fibroblast (OMF) and KB cell growth. PGE2 (0.05-5 micro g/ml) and anti-IL-6 antibody (ab) (50-1000 ng/ml) showed little effect on GK and KB cell growth. Incubation of GK and KB cells with aspirin, anti-IL-6 ab and anti-TNF-alpha ab showed little effect on arecoline- and AN-induced cytotoxicity, cell cycle arrest and apoptosis. Exposure to anti-TNF-alpha ab slightly affected arecoline- and AN-modulated PGE2 and IL-6 production by GK and KB cells. Arecoline- and AN-conditioned medium decreased phytohemagglutinin-mediated CD4+ and CD8+ T cell activation. These results indicate that BQ chewing contributes to the pathogenesis of cancer and OSF by impairing T cell activation and by induction of PGE2, TNF-alpha and IL-6 production, which affect oral mucosal inflammation and growth of OMF and oral epithelial cells.

Areca↗
PubMed1984

Pilot survey of oral mucosa in areca (betel) nut chewers on Hainan Island of the People's Republic of China.

100 people on Hainan Island were studied for their smoking and chewing habits and the condition of their oral mucosa. Ninety-five percent of the study population chewed areca (betel) nut. In men this habit was supplemented with either smoking cigarettes or water pipe. In two men a small commissural leukoplakia was found. In three women clinical and histologic changes pointed towards oral submucous fibrosis.

Adult↗
PubMed2006

Factors associated with quitting areca (betel) quid chewing.

OBJECTIVES: The purpose of this study was to provide useful data for a future abstinence project by identifying the factors related to quitting areca (betel) quid chewing. METHODS: The study was cross-sectional. Data on demographic variables, psychological factors and substance-use behaviors were collected via questionnaires from 326 participants. RESULTS: Multiple logistic regression analysis indicated that the areca/betel quid chewers who were less educated (OR = 0.58, 95% CI = 0.34-0.98) were least likely to try to give up. Among the chewers who tried to quit, those employed as full-time drivers (OR = 2.24, 95% CI = 1.14-4.39), who had drinking habits (OR = 2.41, 95% CI = 1.24-4.66), and who preferred to chew only betel quid wrapped with leaf (OR = 4.44, 95% CI = 1.99-9.90) were more likely to fail. Chewers who successfully quit had a higher internal health locus of control compared with those who failed to quit (one-point increments, OR = 0.94, 95% CI = 0.90-0.98). CONCLUSIONS: The results suggest that health educators and researchers can better influence people's chewing behavior if the importance of chewers' education level, job type, substance use (i.e. drinking habits, type of betel quid), and level of health locus of control are all taken into consideration when devising interventions.

Adult↗
PubMed1990

Effect on the incidence of oral submucous fibrosis of intervention in the areca nut chewing habit.

Incidence of oral submucous fibrosis was calculated from a 10-yr prospective intervention study of 12,212 individuals with a strong component of health education on tobacco and area nut chewing. Based on 11 new cases among 6341 chewers, the annual incidence was 8.0 per 100,000 among men and 29.0 for women. An earlier 10-yr follow-up study, with no intervention component, served as control. Based on 11 new cases among 3,809 chewers, the annual incidence was 21.3 per 100,000 for men and 45.7 for women controls. Although the decrease in the incidence in the intervention cohort was not statistically significant due to small number of cases, the results underscored the causal role of areca nut chewing and indicated the potential for primary prevention of oral submucous fibrosis.

Adolescent↗
PubMed1999

Effects of areca nut, inflorescence piper betle extracts and arecoline on cytotoxicity, total and unscheduled DNA synthesis in cultured gingival keratinocytes.

Betel quid (BQ) chewing has a strong correlation with oral leukoplakia, submucous fibrosis and oral cancer. For elucidation of its pathogenesis, we investigated the effects of areca nut (AN) and inflorescence piper betle (IPB) extracts and arecoline on the growth, total DNA synthesis (TDS) and unscheduled DNA synthesis (UDS) of cultured human gingival keratinocytes (GK). Arecoline and AN extract suppressed the growth of GK over 5 days of incubation in a dose-dependent fashion. At concentrations of 100, 200 and 400 microg/ml, AN extract suppressed the growth of GK by 31%, 46% and 90%, respectively. The IPB extracts exerted less inhibitory effect on the growth of GK. IPB extract (200-400 microg/ml) decreased cell numbers by 20-40% over 5 days of incubation. Moreover, at a concentration of 0.1, 0.2 and 0.4 mM, arecoline suppressed cell growth by 44%, 77% and 96%, respectively. However, only AN extract induced TDS and UDS in cultured GK within 6 h of exposure. Induction of UDS by AN extract was concomitant with the presence of apparent intracellular vacuolization. Arecoline was also toxic to GK, but did not induce intracellular vacuolization. At a concentration range of 200-1600 microg/ml, AN extract induced TDS by 2.1- to 6.5-fold. Furthermore, at a concentration of 400-1600 microg/ml, AN extract elevated the UDS by 2.4- to 5.5-fold more than that of untreated control. On the contrary, IPB extract (200-1600 microg/ml) and arecoline (0.2-1.6 mM) inhibited the TDS and UDS of GK to a different extent. Simultaneous exposure of confluent GK to AN extract, IPB extract and arecoline for 1 to 5 days led to different degrees of cytotoxicity that was dose- and time-dependent. These results indicate that AN, IPB and arecoline take part in the pathogenesis of BQ chewing-related oral mucosal lesions, possibly through both genotoxic and non-genotoxic mechanisms.

Areca↗
PubMed1999

Expression of p53 protein correlates with decreased survival in patients with areca quid chewing and smoking-associated oral squamous cell carcinomas in Taiwan.

Expression of p53 protein was examined in oral squamous cell carcinoma (SCC) from patients who were areca quid (AQ) chewers and/or tobacco smokers, using anti-p53 antibodies with an immunoperoxidase technique. Positive p53 stain was observed in 47 of 81 (58%) cases of oral SCC. p53 overexpression was found to be higher in patients without AQ chewing and smoking habits than in patients with these two habits (80% vs 52%, P=0.076). No significant correlation was found between p53 expression and the patients' age, sex, cancer location, clinical staging, primary tumor TNM status, or histological differentiation of SCC. The Kaplan-Meier analysis showed that the prognosis for patients with p53-negative tumors was significantly better than that for patients with p53-positive tumors (P<0.05). A significant correlation was also observed between positive lymph node status and poor prognosis (P<0.05). These results suggest that p53 may serve as an adjuvant marker of poor survival in patients with oral SCCs in Taiwan.

Adult↗
PubMed1999

Infrequent p53 mutations in patients with areca quid chewing-associated oral squamous cell carcinomas in Taiwan.

Mutations in the conserved regions (exons 5-9) of the p53 gene were investigated in 37 untreated human primary oral squamous cell carcinomas (SCCs) using polymerase chain reaction-single strand conformation polymorphism and DNA sequencing analyses. P53 mutations were detected in 2 of 37 (5.4%) oral SCC cases. One tumor sample (case 23) showed a mis-sense point mutation at codon 177, changing CCC to CTC, which resulted in a substitution of proline to leucine in the p53 protein. The other tumor (case 33) had a point mutation at codon 266, changing GGA to AGA and causing a substitution of glycine to arginine in the p53 protein. These two patients with p53 mutations did not have an areca quid chewing habit. These results suggest that mutations in the p53 gene may not play a role in the pathogenesis of human oral SCCs in Taiwan. Recently, we have shown that positive p53 staining was observed in 47 of 81 (58%) cases of oral SCC. The discrepancies between positive p53 protein staining and the low prevalence of p53 mutation in oral SCCs indicate that other mechanism(s) are involved in p53 overexpression.

Adult↗
PubMed2005

Prenatal exposure to arecoline (areca nut alkaloid) and birth outcomes.

The betel nut is commonly used as a drug by Asian populations. A high prevalence of adverse pregnancy outcomes has been reported in women who chewed betel quid during gestation. The hypothesis that chronic exposure of the fetus to arecoline (the principal alkaloid of the areca nut) is the cause was investigated in a clinical observational study on six newborns from Asian mothers who chewed betel nut during pregnancy.

Areca↗
PubMed2004

In-vitro and in-vivo anti-allergic actions of Arecae semen.

The effects of various extracts from oriental medicinal herbs on mast cell-mediated allergic reactions have been investigated. Among the extracts, Arecae semen was the most potent inhibitor of antigen-induced degranulation in RBL-2H3 mast cells. A. semen inhibited DNP-BSA- and compound 48/80-induced degranulation in RBL-2H3 mast cells with IC(50) values of approximately 53 and 52 microg mL(-1), respectively, and inhibited compound 48/80-induced systemic anaphylaxis by 46% at 300 mg kg(-1) in mice. A. semen also inhibited the expression of TNF-alpha and the activation of mitogen activated protein kinase, ERK1/2, which is critical for the production of inflammatory cytokines in mast cells, as indicated by the suppression of the activating phosphorylation of ERK1/2. These results suggest that A. semen may be useful for the treatment of various immediate and delayed allergic diseases.

Anaphylaxis↗
PubMed1991

The growth inhibition of Streptococcus mutans by 5'-nucleotidase inhibitors from Areca catechu L.

New 5'-nucleotidase inhibitors named NF-86I, NF-86II were recently isolated from the seeds of Areca catechu L. NF-86I and NF86II showed inhibitory effects on the growth of Streptococcus mutans MT8148(c) and Streptococcus mutans MT6715(g), respectively. In addition, these inhibitors could inhibit insoluble glucan formation from sucrose. NF-86I and NF-86II were found to be polyphenolic substances. Some polyphenols such as tannic acid bind non-specifically to proteins (tannic activity). The 5'-nucleotidase inhibitors that we isolated did not show any such activity. However, the growth inhibitory activity and the inhibitory effect on water-insoluble glucan production were equal to tannic acid. It is therefore considered that these inhibitors bind specifically to the bacterial cell surface. Our findings suggest that the 5'-nucleotidase inhibitors NF-86I and NF-86II may be useful anti-plaque preventing agents.

5'-Nucleotidase↗
PubMed1998

Areca nut extract inhibits the growth, attachment, and matrix protein synthesis of cultured human gingival fibroblasts.

Betel quid chewing is a popular oral habit in India, South Africa, and many Southeast Asian countries. The effects of areca nut (AN) extract on the growth, attachment, and protein synthesis of healthy human gingival fibroblasts (GF) were investigated to determine why betel quid (BQ) chewers have higher prevalence of periodontal disease than non-chewers. Twenty-four hour exposure of human GF to AN extract (> 200 microg/ml) in culture led to the formation of numerous intracellular vacuoles. As analyzed by modified MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide] assay, AN extract significantly suppressed the growth of GF over 5 days of incubation in a dose-dependent manner. At concentrations of 50 and 300 microg/ml, AN extract suppressed the growth of GF with 30% and 57% (P < 0.05), respectively. AN extract also significantly suppressed the synthesis of [3H]proline incorporation into trichloroacetic acid (TCA) precipitated proteins. At concentrations of 200, 400, and 600 microg/ml, AN extract suppressed the protein synthesis with 33%, 58%, and 63% of inhibition (P < 0.05), respectively. Preincubation of cells in a medium containing AN extract for 2 hours inhibits the subsequent attachment of cultured GF to type I collagen at the 50% inhibitory concentration (IC50) which is about 720 to 798 microg/ml. Considering the frequent consumption of BQ throughout the day, impairment of sequential fibroblast functions by BQ ingredients is a potential mechanism through which BQ chewing exert a deleterious effect to the gingival tissues.

Areca↗
PubMed2000

Areca nut extract up-regulates prostaglandin production, cyclooxygenase-2 mRNA and protein expression of human oral keratinocytes.

There are about 600 million betel quid (BQ) chewers in the world. BQ chewing is associated with increased incidence of oral cancer and submucous fibrosis. In this study, areca nut (AN) extract (200-800 microg/ml) induced the prostaglandin E(2) (PGE(2)) production by 1. 4-3.4-fold and 6-keto-PGF(1 alpha) production by 1.1-1.7-fold of gingival keratinocytes (GK), respectively, following 24 h of exposure. Exposure of GK to AN extract (>400 microg/ml) led to cell retraction and intracellular vacuoles formation. At concentrations of 800 and 1200 microg/ml, AN extract induced cell death at 21-24 and 32-52% as detected by MTT assay and cellular lactate dehydrogenase release, respectively. Interestingly, AN-induced morphological changes of GK are reversible. GK can still proliferate following exposure to AN extract. Cytotoxicity of AN extract cannot be inhibited by indomethacin (1 microM) and aspirin (50 microM), indicating that prostaglandin (PG) production is not the major factor responsible for AN cytotoxicity. PGE(2) exhibited little effect on the growth of GK at concentrations ranging from 100-1000 pg/ml. Stimulating GK production of PGs by AN extract could be due to induction of cyclooxygenase-2 (COX-2) mRNA expression and protein production. These results suggest that AN ingredients are critical in the pathogenesis of oral submucous fibrosis and oral cancer via their stimulatory effects on the PGs, COX-2 production and associated tissue inflammatory responses. AN cytotoxicity to GK is not directly mediated by COX-2 stimulation and PG production.

6-Ketoprostaglandin F1 alpha↗