Systematic Review of Roles of Arecoline and Arecoline N-Oxide in Oral Cancer and Strategies to Block Carcinogenesis

Abstract

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.

MiR-34a functions as a tumor suppressor in oral cancer through the inhibition of the Axl/Akt/GSK-3β pathway

“…In Taiwan, the primary cause of oral cancer is attributed to betel nut chewing, which has a significant association with the presence of arecoline. 28 Previous studies have indicated a substantial upregulation of β-catenin expression in the epithelium of oral cancer patients with a history of betel nut chewing, and arecoline has been shown to directly induce an increase in β-catenin protein expression. 29 Shiah et al.…”

Effect of skinfold thickness on arm venous access port in cancer patients

“…In recent years, the continuous deterioration of the social environment has affected people's physical health, people's lifestyle and dietary structure have been changed, and cancer patients have been increasing year by year 22,23 . Tumors are defined as vegetations that generate space‐occupying lumpy protrusions in patients due to sudden loss of normal regulation of cells in the body due to various carcinogenic factors 24–26 . Most patients with malignant tumors have bad living habits such as smoking, alcoholism, eating high energy and high fat, or malignant tumors in their tissues caused by exogenous factors such as external environmental stimuli, or malignant tumors in their local tissues caused by endogenous factors such as genetic factors, congenital or acquired immunodeficiency, and endocrine disorders 27 .…”

“… 22 , 23 Tumors are defined as vegetations that generate space‐occupying lumpy protrusions in patients due to sudden loss of normal regulation of cells in the body due to various carcinogenic factors. 24 , 25 , 26 Most patients with malignant tumors have bad living habits such as smoking, alcoholism, eating high energy and high fat, or malignant tumors in their tissues caused by exogenous factors such as external environmental stimuli, or malignant tumors in their local tissues caused by endogenous factors such as genetic factors, congenital or acquired immunodeficiency, and endocrine disorders. 27 The clinical manifestations of patients with malignant tumors are mainly divided into local and systemic manifestations.…”

Bioactive Components of Areca Nut: An Overview of Their Positive Impacts Targeting Different Organs

“…In addition, previous research has reported that several supplements, such as N -acetylcysteine or antioxidants like vitamins, manifest cancer risk reduction. For instance, N -acetylcysteine can conjugate with arecoline and produce mercapturic acid compounds, which are relatively less toxic and excreted through urine [ 196 ]. Thus, the combined use may be a promising strategy to reduce the potential toxicities and side effects of long-term arecoline use.…”