{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T22:39:22Z","timestamp":1792190362923,"version":"4.4.0"},"reference-count":77,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T00:00:00Z","timestamp":1682035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kaohsiung Medical University Research Foundation","award":["KMU-M112018"],"award-info":[{"award-number":["KMU-M112018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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\u2013mesenchymal transition (EMT) inducers such as reactive oxygen species, transforming growth factor-\u03b21, 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.<\/jats:p>","DOI":"10.3390\/cells12081208","type":"journal-article","created":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T10:11:25Z","timestamp":1682071885000},"page":"1208","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Systematic Review of Roles of Arecoline and Arecoline N-Oxide in Oral Cancer and Strategies to Block Carcinogenesis"],"prefix":"10.3390","volume":"12","author":[{"given":"Albert Min-Shan","family":"Ko","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan"},{"name":"Cardiovascular Department, Chang Gung Memorial Hospital, Taoyuan 33302, Taiwan"},{"name":"Health Aging Research Center, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1044-2673","authenticated-orcid":false,"given":"Hung-Pin","family":"Tu","sequence":"additional","affiliation":[{"name":"Department of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7713-9487","authenticated-orcid":false,"given":"Ying-Chin","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Medical Research, China Medical University Hospital, China Medical University, No. 2 Yu-Der Road, Taichung 40447, Taiwan"},{"name":"Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 106216, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"31","DOI":"10.47102\/annals-acadmedsg.V33N4p31S","article-title":"Epidemiology of betel quid usage","volume":"33","author":"Gupta","year":"2004","journal-title":"Ann. 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