Arecoline N-oxide initiates oral carcinogenesis and arecoline N-oxide mercapturic acid attenuates the cancer risk

• Published in: Life sciences (1973) 2021-04, Vol.271, p.119156, Article 119156
• Main Authors: Nithiyanantham, Srinivasan, Arumugam, Sankar, Hsu, Hui-Ting, Chung, Chia-Min, Lee, Chi-Pin, Tsai, Ming-Hsui, Yeh, Kun-Tu, Luo, Shun-Yuan, Ko, Ying-Chin
• Format: Article
• Language: English
• Subjects: Acetylcysteine - therapeutic use; Adult; Animals; ANO; Antioxidants; Arecoline; Arecoline - analogs & derivatives; Arecoline - toxicity; Cancer; Carcinogenesis; Carcinogens; Cell proliferation; Cells, Cultured; Cyclic N-Oxides - toxicity; Cytotoxicity; Depletion; Female; Free Radical Scavengers - therapeutic use; Health risks; Humans; IL-1β; Male; Metabolites; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Mouth Neoplasms - chemically induced; Mouth Neoplasms - metabolism; Mouth Neoplasms - prevention & control; NOM; Notch1 protein; Oral cancer; Oral cavity; Oral squamous cell carcinoma; Oxidative stress; Receptor, Notch1 - antagonists & inhibitors; Receptor, Notch1 - biosynthesis; Squamous cell carcinoma; Toxicity; Tumor Cells, Cultured; Tumors
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2021.119156

Arecoline N-oxide (ANO), an oxidative metabolite of the areca nut, is a predictable initiator in carcinogenesis. The mechanisms of arecoline metabolites in human cancer specimens is still limited. This present study aims to estimate the oral squamous cell carcinoma (OSCC) inductive activity between arecoline metabolites in human cancer specimens/OSCC cells. We have collected 22 pairs (tumor and non-tumor part) of patient's specimens and checked for clinical characteristics. The identification of arecoline and its metabolites levels by using LC-MS/MS. The NOD/SCID mice model was used to check the OSCC inductive activity. The tumor part of OSCC samples exhibited higher levels of arecoline and ANO. Besides, ANO treated mice accelerates the NOTCH1, IL-17a and IL-1β expressions compared to the control mice. ANO exhibited higher cytotoxicity, intracellular ROS levels and decline in antioxidant enzyme levels in OC-3 cells. The protein expression of NOTCH1 and proliferation marker levels are significantly lower in NOM treated cells. Overall, ANO induced initial stage carcinogenesis in the oral cavity via inflammation, ROS and depletion of antioxidant enzymes. Arecoline N-oxide mercapturic acid (NOM) attenuates the initiation of oral carcinogenesis.