Areca nut is a recently confirmed classⅠcarcinogen. The areca nut chewing habit is a primary environmental risk factor for the development of oral cancer due to cytotoxicity, genotoxicity, mutagenicity, and carcinogenicity of arecoline(ARC), areca-containing tannins, areca-specific nitrosamine(ASNA), and reactive oxygen species(ROS) produced during areca nut chewing. ARC is capable of inducing apoptosis of oral fibroblasts, keratinocytes, and human umbilical vein endothelial cells. The results of different types of short-term screening tests differ, so the genotoxicity and mutagenicity of areca-containing tannins remain controversial. Tannin-containing polyphenolic fraction is a primary carcinogenic ingredient. 3-Methyl-nitrosamino propionaldehyde can induce DNA strand breakage and DNA-protein crosslinkage for human buccal keratinocytes. 3-Methyl-nitrosamino propionitrile is a potent carcinogen that can induce nasal, esophageal, and tongue tumors in laboratory animals. ROS produced during areca nut chewing can promote tumorigenesis by inducing DNA oxidative damage and activating oncogenes. A newly found proteoglycan in the 3.0×104 to 10.0× 104 relative molecular mass fraction of areca nut extract induces oxidative stress and modulates a signaling cascade that upregulates hypoxia, inducing factor-1α expression in oral cancer cells, which eventually leads to autophagy. Autophagy can help cancer cells survive ARC-induced apoptosis and promote the development of oral cancer. Areca nut extract can enhance tongue cancer cell-induced platelet aggregation by generating ROS, thus promoting tongue cancer metastasis.
