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Betel quid and areca nut are complex mixture carcinogens, but little is known about whether their derived single-agent arecoline or arecoline N-oxide (ANO) is carcinogenic, and the underlying mechanisms remain unclear. In this systematic review, we analyzed recent studies on the roles of arecoline and ANO in cancer and strategies to block carcinogenesis. In the oral cavity, flavin-containing monooxygenase 3 oxidizes arecoline to ANO, and both alkaloids conjugate with N-acetylcysteine to form mercapturic acid compounds, which are excreted in urine, reducing arecoline and ANO toxicity. However, detoxification may not be complete. Arecoline and ANO upregulated protein expression in oral cancer tissue from areca nut users compared to expression levels in adjacent normal tissue, suggesting a causal relationship between these compounds and oral cancer. Sublingual fibrosis, hyperplasia, and oral leukoplakia were diagnosed in mice subjected to oral mucosal smearing of ANO. ANO is more cytotoxic and genotoxic than arecoline. During carcinogenesis and metastasis, these compounds increase the expression of epithelial–mesenchymal transition (EMT) inducers such as reactive oxygen species, transforming growth factor-β1, Notch receptor-1, and inflammatory cytokines, and they activate EMT-related proteins. Arecoline-induced epigenetic markers such as sirtuin-1 hypermethylation, low protein expression of miR-22, and miR-886-3-p accelerate oral cancer progression. Antioxidants and targeted inhibitors of the EMT inducers used reduce the risk of oral cancer development and progression. Our review findings substantiate the association of arecoline and ANO with oral cancer. Both of these single compounds are likely carcinogenic to humans, and their mechanisms and pathways of carcinogenesis are useful indicators for cancer therapy and prognosis. [ABSTRACT FROM AUTHOR]

Abstract Background Areca nut chewing has been reported to be associated with obesity, metabolic syndrome, hypertension, and cardiovascular mortality in previous studies. The aim of this study was to examine whether chewing areca nut increases the risk of coronary artery disease (CAD) in Taiwanese men. Methods This study is a hospital-based case-control study. The case patients were male patients diagnosed in Taiwan between 1996 and 2009 as having a positive Treadmill exercise test or a positive finding on the Thallium-201 single-photon emission computed tomography myocardial perfusion imaging. The case patients were further evaluated by coronary angiography to confirm their CAD. Obstructive CAD was defined as a ≥ 50% decrease in the luminal diameter of one major coronary artery. The patients who did not fulfill the above criteria of obstructive CAD were excluded. The potential controls were males who visited the same hospital for health check-ups and had a normal electrocardiogram but no history of ischemic heart disease or CAD during the time period that the case patients were diagnosed. The eligible controls were randomly selected and frequency-matched with the case patients based on age. Multiple logistic regression analyses were used to estimate the odds ratio of areca nut chewing and the risk of obstructive CAD. Results A total of 293 obstructive CAD patients and 720 healthy controls, all men, were analyzed. Subjects who chewed areca nut had a 3.5-fold increased risk (95% CI = 2.0-6.2) of having obstructive CAD than those without, after adjusting for other significant covariates. The dose-response relationship of chewing areca nut and the risk of obstructive CAD was also noted. After adjusting for other covariates, the 2-way additive interactions for obstructive CAD risk were also significant between areca nut use and cigarette smoking, hypertension and dyslipidemia. Conclusions Long-term areca nut chewing was an independent risk factor of obstructive CAD in Taiwanese men. Interactive effects between chewing areca nut and cigarette smoking, hypertension, and dyslipidemia were also observed for CAD risk. Further exploration of their underlying mechanisms is necessary.

Areca nut has been evaluated as a group I carcinogen to humans. However, the exact compounds of areca nut causing oral cancer remain unproven. Previous findings from our lab revealed that arecoline N‐oxide (ANO), a metabolite of arecoline, exhibits an oral fibrotic effect in immune‐deficient NOD/SCID mice. The aim of this study is to investigate the oral potentially malignant disorders (OPMD) inductive activity between areca‐alkaloid arecoline and its metabolite ANO in C57BL/6 mice. Our findings show that ANO showed higher activity in inducing hyperplasia with leukoplakia and collagen deposition in C57BL/6 mice compared with the arecoline treated groups. Importantly, immunohistochemical studies showed significant upregulation of NOTCH1, HES1, FAT1, PCNA, and Ki67 expressions in the pathological hyperplastic part. In addition, in vitro studies showed that upregulation of NOTCH1 and FAT1 expressions in ANO treated HGF‐1 and DOK cell models. We found that NOTCH1 regulates TP53 expression from NOTCH1 knockdown oral cancer cells. The DNA damage was significantly increased after arecoline and ANO treatment. Further, we found that arecoline‐induced H2AX expression was regulated by FMO3. Altogether, our findings show that ANO exhibited higher toxicity in OPMD activity and play a significant role in the induction of areca nut mediated oral tumorigenesis. [ABSTRACT FROM AUTHOR]

Aim: We present a systematic review of substance use disorder (SUD) to Areca catechu nut (AN) and AN containing betel quid (ANcBQ) with emphasis on dependence resulting from chewing of tobacco-free ANcBQ. We examined pharmacology of intoxication and addiction, and factors influencing quitting strategies.Methods: Epidemiological publications of SUD were included according to PRISMA criteria. Pharmacological publications were retrieved from the PUBMED database and websites of the WHO, United Nations, and Sigma-Aldrich.Results: Nine epidemiological studies show clear evidence of abuse and dependence in tobacco-free ANcBQ and/or ANcBQ+Tobacco chewers. Dependency is greater if ANcBQ contains tobacco. In both groups higher dependency scores were positively correlated with higher frequency of chewing. Dependency on AN+Lime is associated with altered brain morphology, resting state brain activity, neurochemistry and deterioration of working spatial memory. ANcBQ contains a complex mixture of neuroactive compounds that have the potential to act directly upon all major cerebral neurotransmitter systems. Of these compounds, only arecoline (muscarinic agonist) has been the focus of limited pharmacological investigation. In animal studies, arecoline increases dopamine transmission in the mesocorticolimbic circuit and this action may be one factor contributing to ANcBQ dependency in humans. Societal and familial acceptance of ANcBQ consumption is paramount for commencement and persistence of chewing.Conclusions: ANcBQ SUD remains an orphan disease. The limited understanding of pharmacological basis of intoxication and SUD determines there are no pharmacological replacement therapies for ANcBQ SUD. The addictive properties of ANcBQ coupled with social acceptance of ANcBQ chewing limits the effectiveness of counseling-based quitting programs. [ABSTRACT FROM AUTHOR]

Aims Betel-quid ( BQ) contains biologically psychoactive ingredients; however, data are limited concerning the symptoms and syndrome of BQ dependence among chewers. The aims of this study were to evaluate the ingredients-associated BQ dependence syndrome and country-specific chewing features and behaviour for BQ dependence among chewers from six Asian communities. Design An intercountry Asian Betel-quid Consortium study. Setting Six Asian general communities in Taiwan, Mainland China, Indonesia, Malaysia, Sri Lanka and Nepal. Participants Six multi-stage random samples of BQ chewers in the Asian Betel-quid Consortium study ( n = 2078). Measurements All chewers were evaluated for BQ dependence using the DSM-IV and ICD-10 criteria. Findings The 12-month BQ dependence rate was 12.5-92.6% and 47.9-99.3% ( P = 0.023) among tobacco-free and tobacco-added BQ chewers across the six Asian communities, with a higher dependence rate in chewers who used tobacco-free BQ with lime added than without (23.3-95.6% versus 4.0%, P ≤ 0.001). Taiwanese and Hunanese BQ chewers both notably endorsed the dependency domain of 'time spent chewing'. 'Tolerance' and 'withdrawal' were the major dependence domains associated with the Nepalese and Indonesian chewers, with high BQ dependence rates. Malaysian and Sri Lankan chewers formed a BQ dependence cluster linked closely to 'craving'. In Sri Lanka, the quantity consumed explained 90.5% ( P < 0.001) of the excess dependence risk for tobacco-added use, and could be a mediator between tobacco-derived psychoactive effect and BQ dependence development. Conclusions DSM-IV criteria for dependence apply to a significant proportion of betel quid users in Asian communities, more so if they use it with tobacco or lime. [ABSTRACT FROM AUTHOR]

Little is known about any consequences of swallowing tobacco-free betel-quid (TF-BQ) juice/remnants following chewing and its carcinogenic impact on the upper aerodigestive tract (UADT) to gastrointestinal tract (GIT). We investigated the neoplastic impact of TF-BQ on different anatomical locations along UADT and GIT, and differences according to their histological categories. We conducted a multicenter case-control study examining patients with 2,163 pathology-proven UADT and GIT cancers, comparing them with 2,250 control subjects. Generalized additive models, piecewise regression and polytomous logistic models were applied to identify possible dose-dependent structures and cancer risks. Contrary to nonsignificant GIT-adenocarcinoma risk (aOR = 0.9), TF-BQ users experienced a 1.7- to 16.2-fold higher risk of UADT-squamous cell carcinomas than nonusers, with the peak risk discovered in oral neoplasms. We separately observed a curvilinear and linear TF-BQ dose-risk relationship in oral/pharyngeal/esophageal and laryngeal cancers. Chewers of betel inflorescence were generally at a greater UADT cancer risk. A higher first-piecewise increased risk of esophageal cancer was recognized among areca-fluid swallowers than among nonswallowers (continuous aOR = 1.12 vs. 1.03). TF-BQ use accounted for 66.1-78.7% and 17.8-33.2% of the cases of oral/pharyngeal and esophageal/laryngeal cancers, respectively. However, a reduction from heavy TF-BQ consumption to low-to-moderate consumption only reduced 11.3-34.6% of etiologic fraction of oral/pharyngeal cancers. Alcohol supra-additively modified the risk of TF-BQ in determining the development of oral, pharyngeal and esophageal cancers. In conclusion, the interplay of TF-BQ and alcohol/tobacco use, combined with how chewing habit is practiced, influences carcinogenic consequences on anatomically diverse sites of UADT and GIT cancers, and histologically different types. [ABSTRACT FROM AUTHOR]

Previous investigations have shown that areca nut extracts (ANE) or arecoline (ARE) causes DNA damage, which in turn contributes to oral cell carcinogenesis. To understand the role of microRNA (miRNA) in ANE-associated carcinogenesis, miRNA expression profile was examined in ANE-treated normal human oral fibroblasts. Among the miRNAs changed by ANE exposure, we found that ANE-induced miR-23a overexpression was correlated with an increase of γ-H2AX, a DNA damage marker. In addition, DNA double-strand breaks (DSB) repair that was determined by an in vivo plasmid-based assay was reduced in ANE-treated or miR-23a–overexpressed cells, suggesting the role of miR-23a in DSB repair. FANCG is one of Fanconi anemia susceptibility genes that participate in DSB repair pathway to prevent chromosomal aberrations. FANCG was predicted as a candidate target of miR-23a by TargetScan algorithm. This was confirmed by ectopic overexpression or knockdown of miR-23a. The correlation between miR-23a overexpression and areca nut–chewing habit could also be found in oral cancer patients. Finally, we showed that ANE-induced/ARE-induced miRNAs were significantly associated with the functional categories of “genetic disorders” and “cancer” using network-based analyses. In conclusion, our data showed for the first time that ANE-induced miR-23a was correlated with a reduced FANCG expression and DSB repair, which might contribute to ANE-associated human malignancies. [ABSTRACT FROM AUTHOR]

This study is first to analyze the inflammatory cytokines, produced by the bronchial epithelium after exposure to areca nut extract (ANE), which contribute to airway remodeling by increasing human bronchial smooth muscle cells (BSMC) migration and proliferation. We treated human bronchial epithelial cell lines BEAS-2B and HBE135-E6E7 (HBE) with ANE, saliva-reacted ANE (sANE), and the areca alkaloids arecoline and then harvested the conditioned medium (CM) that was added to BSMC. Exposure of BEAS-2B and HBE to ANE, sANE, and arecoline increased interleukin 8 (IL-8) and Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) production. Cultures of BSMC with ANE-, sANE-, and arecoline-BEAS-2B-CM and -HBE-CM increased BSMC proliferation and migration. Induction of BSMC proliferation and migration by sANE-BEAS-2B-CM and -HBE-CM was associated with increased phosphorylation of Raf, MEK1/2, and extracellular signal regulated kinase (ERK)1/2 and the upregulation of krüppel-like factor 5 (KLF5), cyclin D, and integrin-linked kinase. Blocking ERK1/2 by a specific inhibitor significantly decreased BSMC proliferation and migration by inhibiting KLF5 enhancement. KLF5 knockdown also decreased sANE-BEAS-2B-CM, sANE-HBE-CM, and recombinant human interleukin 8/recombinant human RANTES–mediated BSMC proliferation and migration, suggesting that KLF5 was involved in the regulation of BSMC proliferation and migration. Our study suggests that inhibition of IL-8 and RANTES or IL-8/RANTES-mediated mitogen-activated protein kinase/KLF5 signaling is an attractive therapeutic target for areca nut–induced asthma. [ABSTRACT FROM AUTHOR]

Areca nut (AN) was identified as carcinogenic to humans. Around 600 million people globally use AN in some form, yet no effective therapeutic drug is available to overcome AN addiction. This preclinical study examines the effects of antidepressants on AN use with animal models. We produced AN powder and dissolved it into drinking water, training 55 C57BL/6 mice in free self-selection to drink AN water or normal water. Then, the mice were randomly divided into four groups. Selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants (TCAs) were given as three treatment groups and one placebo group for four weeks. In the follow-up period, the preference and amount of free selection of AN and normal water, and oral pathological change were evaluated. There was a significant decrease in preference for AN drinking during the first four weeks, and the 36th week after drug withdrawal in the MAOI and SSRI groups (all p < 0.05). The drug-reducing effect of AN water in the 1–4-week period was significant in the MAOI group (p < 0.0001) and was also significant in the 3–4-week period in the SSRI group (p = 0.03). The TCA group did not show a decrease effect. At the endpoint (60 weeks), oral mucosal fibrosis (OSF) levels and risk in the SSRI (p = 0.0081) and MAOI (p = 0.01) groups were significantly lower than those in the control group. Antidepressant drugs MAOIs and SSRIs could reduce the amount of AN use and decrease the early stage of oral fibrosis in mice, but SSRIs may need to be boosted again. [ABSTRACT FROM AUTHOR]

Some studies indicate that betel quid and its ingredients chewing can produce cell mutagenicity and tumorigenicity. In Taiwan studies, betel quid chewing is the main cause of' submucous fibrosis and oral cancer. Understanding the distribution and characteristics of the areca nut, chewing population is one of the first steps in the effort to prevent these oral diseases. A stratified cluster random sample of 2442 junior high school students in Changhua county, Taiwan, were surveyed for the habit of areca nut chewing. Significantly more male students chewed areca nut than female students (9.2% vs 0.9%). The proportion of students who were chewing Areca nuts increased with increasing (seventh to ninth) grades. Areca nut was used by junior high school students at a higher rate in village (rural) areas as compared to town (semi-urban) and city (urban) areas (6.4%, 3.7% and 3.0%, respectively). More students in the ordinary achievement classes were chewing areca nuts than those in the high achievement classes (8.4% vs 1.6%). Areca nut chewing students tended to have users in their families. Cigarette smoking and alcohol drinking were positively associated with areca nut chewing. More than half (53.6%) of the areca nut chewing students first experimented with this habit with a family member, most often the father or grandfather. [ABSTRACT FROM AUTHOR]

Abstract: In considering documented developmental toxicity and teratogenicity found in earlier research, maternal betel quid chewing may very well be linked to a higher risk of adverse birth outcomes. The aim of this study was to investigate the significance of betel quid chewing, together with the use of cigarettes or alcohol, either independently or combined, on birth-related outcomes. A total of 1264 aboriginal women who had just given birth in 10 hospitals in Southern and Eastern Taiwan were recruited. Information on their maternal and newborn characteristics was obtained from medical charts and by performing personal interviews using a validated questionnaire. Maternal areca nut chewing during pregnancy was found to be significantly associated with both birth weight loss (−89.54g) and birth length reduction (−0.43cm). A significantly lower male newborn rate (aOR=0.62) was observed among aboriginal women with a habit of betel quid chewing during pregnancy. The use of this substance conveyed a 2.40- and 3.67-fold independent risk of low birth weight and full-term low birth weight, respectively. An enhanced risk (aOR=3.26–5.99) of low birth weight was observed among women concomitantly using betel quid, cigarette and alcohol during gestation. Our findings suggest that betel quid chewing during pregnancy has a substantial effect on a number of birth outcomes, including sex ratio at birth, lower birth weight and reduced birth length. [Copyright &y& Elsevier]

In the present study, we investigated the effect of arecoline, a major areca nut alkaloid, on the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced activation of cytochrome P4501A1 (CYP1A1) in a human hepatoma cell line Huh-7. We treated Huh-7 cells with 10nM TCDD in the presence of different concentrations of arecoline (50–300μM). Our results indicated that arecoline attenuated the TCDD-induced CYP1A1 enzyme activation with an inhibitory effect on cell proliferation. By using real-time RT-PCR, we demonstrated that arecoline inhibited the TCDD-induced activations of CYP1A1 and AhR repressor (AhRR) mRNA expression in a similar pattern. Our results revealed that arecoline inhibited AhR mRNA expression with no direct effect on CYP1A1 enzyme activity. Therefore, in our present study, the observed inhibitory effect of arecoline on CYP1A1 activation was not due to the up-regulation of AhRR or direct inhibitory effect on CYP1A1. Taken together, here we have demonstrated that arecoline attenuates the TCDD-induced CYP1A1 activation mainly via down-regulation of AhR expression in human hepatoma cells, suggesting the possible involvement of arecoline in the AhR-mediated metabolism of environmental toxicants in liver. [Copyright &y& Elsevier]