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.