Prague Med. Rep. 2020, 121, 209-235

A Review on Role of Arecoline and Its Metabolites in the Molecular Pathogenesis of Oral Lesions with an Insight into Current Status of Its Metabolomics

Aparajita Das, Sarbani Giri

Laboratory of Molecular and Cell Biology, Department of Life Science and Bioinformatics, Assam University, Silchar, India

Received June 5, 2018
Accepted November 9, 2020


1. Angadi, P. V., Kale, A. D., Hallikerimath, S. (2011) Evaluation of myofibroblasts in oral submucous fibrosis: correlation with disease severity. J. Oral Pathol. Med. 40, 208–213. <>
2. Boyland, E., Nery, R. (1969) Mercapturic acid formation during the metabolism of arecoline and arecaidine in rat. Biochem. J. 113, 123–130. <>
3. Boyland, E., Nice, E., Williams, K. (1971) The catalysis of nitrosation by thiocyanate from saliva. Food Cosmet. Toxicol. 9(5), 639–643. <>
4. Camilli, T. C., Weeraratna, A. T. (2010) Striking the target in Wnt-y conditions: Intervening in Wnt signalling during cancer progression. Biochem. Pharmacol. 80, 702–711. <>
5. Chang, M. C., Chan, C. P., Wang, W. T., Chang, B. E., Lee, J. J., Tseng, S. K., Yeung, S. Y., Hahn, L. J., Jeng, J. H. (2013a) Toxicity of areca nut ingredients: Activation of CHK1/CHK2, induction of cell cycle arrest, and regulation of MMP-9 and TIMPs production in SAS epithelial cells. Head Neck 35, 1295–1302. <>
6. Chang, M. C., Lin, L. D., Wu, H. L., Ho, Y. S., Hsien, H. C., Wang, T. M., Jeng, P. Y., Cheng, R. H., Hahn, L. J., Jeng, J. H. (2013b) Areca nut-induced buccal mucosa fibroblast contraction and its signalling: A potential role in oral submucous fibrosis – a precancer condition. Carcinogenesis 34, 1096–1104. <>
7. Chang, Y. C., Yang, S. F., Tai, K. W., Chou, M. Y., Hsieh, Y. S. (2002a) Increased tissue inhibitor of metalloproteinase-1 expression and inhibition of gelatinase A activity in buccal mucosal fibroblasts by arecoline as possible mechanisms for oral submucous fibrosis. Oral Oncol. 38, 195–200. <>
8. Chang, Y. C., Tsai, C. H., Tai, K. W., Yang, S. H., Chou, M. Y., Lii, C. K. (2002b) Elevated vimentin expression in buccal mucosal fibroblasts by arecoline in vitro as a possible pathogenesis for oral submucous fibrosis. Oral Oncol. 38, 425–430. <>
9. Chang, Y. C., Tsai, C. H., Lai, Y. L., Yu, C. C., Chi, W. Y., Li, J. J., Chang, W. W. (2014) Arecoline-induced myofibroblast transdifferentiation from human buccal mucosal fibroblasts is mediated by ZEB1. J. Cell. Mol. Med. 18, 698–708. <>
10. Chen, Y. C., Chen, B. C., Yu, C. C., Lin, S. H., Lin, C. H. (2016) miR-19a, -19b, and -26b mediate CTGF expression and pulmonary fibroblast differentiation. J. Cell. Physiol. 231, 2236–2248. <>
11. Chiang, S. L., Jiang, S. S., Wang, Y. J., Chiang, H. C., Chen, P. H., Tu, H. P., Ho, K. Y., Tsai, Y. S., Chang, I. S., Ko, Y. C. (2007) Characterization of arecoline-induced effects on cytotoxicity in normal human gingivial fibroblasts by global gene expression profiling. Toxicol. Sci. 100(1), 66–74. <>
12. Cox, S., Vickers, E. R., Ghu, S., Zoellner, H. (2010) Salivary arecoline levels during areca nut chewing in human volunteers. J. Oral Pathol. Med. 39, 465–469. <>
13. Dasgupta, R., Saha, I., Pal, S., Bhattacharyya, A., Sa, G., Nag, T. C., Das, T., Maiti, B. R. (2006) Immunosuppression, hepatotoxicity and depression of antioxidant status by arecoline in albino mice. Toxicology 227, 94–104. <>
14. Deb, S., Chatterjee, A. (1998) Influence of buthionine sulfoximine and reduced glutathione on arecoline-induced chromosomal damage and sister chromatid exchange in mouse bone marrow cells in vivo. Mutagenesis 13, 243–248. <>
15. Deng, Y. T., Chen, H. M., Cheng, S. J., Chiang, C. P., Kuo, M. Y. P. (2009) Arecoline-stimulated connective tissue growth factor production in human buccal mucosal fibroblasts: Modulation by curcumin. Oral Oncol. 45, e99–e105. <>
16. Eckert, A. W., Wickenhauser, C., Salins, P. C., Kappler, M., Bukur, J., Seliger, B. (2016) Clinical relevance of the tumor microenvironment and immune escape of oral squamous cell carcinoma. J. Transl. Med. 14, 85. <>
17. Eickelberg, O., Köhler, E., Reichenberger, F., Bertschin, S., Woodtli, T., Eme, P., Perruchoud, A. P., Roth, M. (1999) Extracellular matrix deposition by primary human lung fibroblasts in response to TGF-beta1 and TGF-beta3. Am. J. Physiol. 276(5), 814–824.
18. Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D. M., Forman, D., Bray, F. (2015) Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–E386. <>
19. Giri, S., Idle, J. R., Chen, C., Zabriskie, T. M., Krausz, K. W., Gonzalez, F. J. (2006) A metabolomic approach to the metabolism of the areca nut alkaloids arecoline and arecaidine in the mouse. Chem. Res. Toxicol. 19(6), 818–827. <>
20. Giri, S., Krausz, K. W., Idle, J. R., Gonzalez, F. J. (2007) The metabolomics of (±)-arecoline 1-oxide in the mouse and its formation by human flavin-containing monooxygenases. Biochem. Pharmacol. 73(4), 561–573. <>
21. Giri, S., Poindexter, K. M., Sundar, S. N., Firestone, G. L. (2010) Arecoline induced disruption of expression and localization of the tight junctional protein ZO-1 is dependent on the HER 2 expression in human endometrial Ishikawa cells. BMC Cell Biol. 11, 53. <>
22. Griffin, M., Casadio, R., Bergamini, C. M. (2002) Transglutaminases: Nature’s biological glues. Biochem. J. 368, 377–396. <>
23. Harvey, W., Scutt, A., Meghji, S., Canniff, J. P. (1986) Stimulation of human buccal mucosa fibroblasts in vitro by betel-nut alkaloids. Arch. Oral Biol. 31(1), 45–49. <>
24. Hayakawa, T. (1977) Glutathione S-transferases in the metabolism of foreign compounds. Ecotoxicol. Environ. Saf. 1(3), 305–309. <>
25. Higgins, D. F., Biju, M. P., Akai, Y., Wutz, A., Johnson, R. S., Haase, V. H. (2004) Hypoxic induction of Ctgf is directly mediated by Hif-1. Am. J. Physiol. Renal Physiol. 287, 1223–1232. <>
26. Ho, C. M., Hu, F. W., Lee, S. S., Shieh, T. M., Yu, C. H., Lin, S. S., Yu, C. C. (2015) ZEB1 as an indicator of tumor recurrence for areca quid chewing-associated oral squamous cell carcinomas. J. Oral Pathol. Med. 44, 693–698. <>
27. Hsieh, Y. P., Chen, H. M., Chang, J. Z. C., Chiang, C. P., Deng, Y. T., Kuo, M. Y. P. (2015) Arecoline stimulated early growth response-1 production in human buccal fibroblasts: Suppression by epigallocatechin-3-gallate. Head Neck 37, 493–497. <>
28. Hsieh, Y. P., Chen, H. M., Lin, H. Y., Yang, H., Chang, J. Z. C. (2017) Epigallocatechin-3-gallate inhibits transforming-growth-factor-β1-induced collagen synthesis by suppressing early growth response-1 in human buccal mucosal fibroblasts. J. Formos. Med. Assoc. 116, 107–113. <>
29. Hsu, Y. H., Liu, W. H., Chen, W., Kuo, Y. C., Hsiao, C. Y., Hung, P. H., Jong, I. C., Chiang, P. C., Hsu, C. C. (2011) Association of betel nut chewing with chronic kidney disease: A retrospective 7-year study in Taiwan. Nephrology (Carlton) 16, 751–757. <>
30. Hu, F. W., Lee, S. S., Yang, L. C., Tsai, C. H., Wang, T. H., Chou, M. Y., Yu, C. C. (2015) Knockdown of S100A4 impairs arecoline-induced invasiveness of oral squamous cell carcinomas. Oral Oncol. 51, 690–697. <>
31. Hu, W. C., Chang, Y. Z., Wang, H. W., Chao, M. R. (2010) High-throughput simultaneous analysis of five urinary metabolites of areca nut and tobacco alkaloids by isotope-dilution liquid chromatography-tandem mass spectrometry with on line solid phase extraction. Cancer Epidemiol. Biomarkers Prev. 19(10), 2570–2581. <>
32. Huang, L. W., Hsieh, B. S., Cheng, H. L., Hu, Y. C., Chang, W. T., Chang, K. L. (2012) Arecoline decreases interleukin-6 production and induces apoptosis and cell cycle arrest in human basal cell carcinoma cells. Toxicol. Appl. Pharmacol. 258, 199–207. <>
33. Hung, S. P., Yang, M. H., Tseng, K. F., Lee, O. K. (2013) Hypoxia-induced secretion of TGF-β1 in mesenchymal stem cell promotes breast cancer cell progression. Cell Transplant. 22, 1869–1882. <>
34. Hung, T. C., Huang, L. W., Su, S. J., Hsieh, B. S., Cheng, H. L., Hu, Y. C., Chen, Y. H., Hwang, C. C., Chang, K. L. (2011) Hemeoxygenase-1 expression in response to arecoline-induced oxidative stress in human umbilical vein endothelial cells. Int. J. Cardiol. 151, 187–194. <>
35. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (2004) Betel-quid and areca-nut chewing and some areca-nut-derived nitrosamines. IARC Monogr. Eval. Carcinog. Risks Hum. 85, 1–334.
36. Jeng, J. H., Wang, Y. J., Chiang, B. L., Lee, P. H., Chan, C. P., Ho, Y. S., Wang, T. M., Lee, J. J., Hahn, L. J., Chang, M. C. (2003) Roles of keratinocyte inflammation in oral cancer: Regulating the prostaglandin E2, interleukin-6 and TNF-α production of oral epithelial cells by areca nut extract and arecoline. Carcinogenesis 24, 1301–1315. <>
37. Ji, W. T., Yang, S. R., Chen, J. Y. F., Cheng, Y. P., Lee, Y. R., Chiang, M. K., Chen, H. R. (2012) Arecoline downregulates levels of p21 and p27 through the reactive oxygen species/mTOR complex 1 pathway and may contribute to oral squamous cell carcinoma. Cancer Sci. 103, 1221–1229. <>
38. Jobling, M. F., Mott, J. D., Finnegan, M. T., Jurukovski, V., Erickson, A. C., Walian, P. J., Taylor, S. E., Ledbetter, S., Lawrence, C. M., Rifkin, D. B., Barcellos-Hof, M. H. (2006) Isoform-specific activation of latent transforming growth factor beta (LTGF-beta) by reactive oxygen species. Radat. Res. 166, 839–848. <>
39. Jung, S. N., Yang, W. K., Kim, J., Kim, H. S., Kim, E. J., Yun, H., Park, H., Kim, S. S., Choe, W., Kang, I., Ha, J. (2008) Reactive oxygen species stabilize hypoxia-inducible factor-1 alpha protein and stimulate transcriptional activity via AMP-activated protein kinase in DU145 human prostate cancer cells. Carcinogenesis 29(4), 713–721. <>
40. Kademani, D. (2007) Oral cancer. Mayo Clin. Proc. 82(7), 878–887. <>
41. Kao, S. Y., Wu, C. H., Lin, S. C., Yap, S. K., Chang, C. S., Wong, Y. K., Chi, L. Y., Liu, T. Y. (2002) Genetic polymorphism of cytochrome P4501A1 and susceptibility to oral squamous cell carcinoma and oral precancer lesions associated with smoking/betel use. J. Oral Pathol. Med. 31(9), 505–511. <>
42. Kam, Y., Quaranta, V. (2009) Cadherin-bound β-catenin feeds into the Wnt pathway upon adherens junction dissociation: Evidence for an intersection between β-catenin pools. PLoS One 4(2), e4580. <>
43. Kamath, V. V., Krishnamurthy, S., Satelur, K. P., Rajkumar, K. (2015) Transforming growth factor-β1 and TGF-β2 act synergistically in the fibrotic pathway in oral submucous fibrosis: An immunohistochemical observation. Indian J. Med. Paediatr. Oncol. 36(2), 111–116. <>
44. Ko, Y. C., Chang, P. Y., Kuo, T. M., Chen, P. K., Lin, Y. Z., Hua, C. H., Chen, Y. C. (2018) Arecoline N-oxide up-regulates caspase-8 expression in oral hyperplastic lesions of mice. J. Agric. Food Chem. 65(47), 10197–10205.
45. Krueger, S. K., Williams, D. E. (2005) Mammalian flavin containing monooxygenases: Structure/function, genetic polymorphisms and role in drug metabolism. Pharmacol. Ther. 106(3), 357–387. <>
46. Kuo, T. M., Luo, S. Y., Chiang, S. L., Yeh, K. T., Hsu, H. T., Wu, C. T., Lu, C. Y., Tsai, M. H., Chang, J. G., Ko, Y. C. (2015) Fibrotic effects of arecoline N-oxide in oral potentially malignant disorders. J. Agric. Food Chem. 63(24), 5787–5794. <>
47. Lamouille, S., Xu, J., Derynck, R. (2014) Molecular mechanisms of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 15, 178–196. <>
48. Lee, C. H., Liu, S. Y., Lin, M. H., Chiang, W. F., Chen, T. C., Huang, W. T., Chou, D. S., Chiu, C. T., Liu, Y. C. (2008) Upregulation of matrix metalloproteinase-1 (MMP-1) expression in oral carcinomas of betel quid (BQ) users: Roles of BQ ingredients in the acceleration of tumour cell motility through MMP-1. Arch. Oral Biol. 53, 810–818. <>
49. Lee, P. H., Chang, M. C., Chang, W. H., Wang, T. M., Wang, Y. J., Hahn, L. J., Ho, Y. S., Lin, C. Y., Jeng, J. H. (2006) Prolonged exposure to arecoline arrested human KB epithelial cell growth: Regulatory mechanisms of cell cycle and apoptosis. Toxicology 220, 81–89. <>
50. Lee, S. S., Tsai, C. H., Ho, Y. C., Chang, Y. C. (2008a) The upregulation of heat shock protein 70 expression in areca quid chewing-associated oral squamous cell carcinomas. Oral Oncol. 44, 884–890. <>
51. Lee, S. S., Yang, S. F., Ho, Y. C., Tsai, C. H., Chang, Y. C. (2008b) The upregulation of metallothionein-1 expression in areca quid chewing-associated oral squamous cell carcinomas. Oral Oncol. 44, 180–186. <>
52. Lee, S. S., Yang, S. F., Tsai, C. H., Chou, M. C., Chou, M. Y., Chang, Y. C. (2008c) Upregulation of heme oxygenase-1 expression in areca-quid-chewing-associated oral squamous cell carcinoma. J. Formos. Med. Assoc. 107, 355–363. <>
53. Lee, S. S., Tsai, C. H., Yang, S. F., Ho, Y. C., Chang, Y. C. (2010) Hypoxia inducible factor-1α expression in areca quid chewing-associated oral squamous cell carcinomas. Oral Dis. 16, 696–701. <>
54. Lee, S. S., Tseng, L. H., Li, Y. C., Tsai, C. H., Chang, Y. C. (2011) Heat shock protein 47 expression in oral squamous cell carcinomas and up-regulated by arecoline in human oral epithelial cells. J. Oral Pathol. Med. 40, 390–396. <>
55. Lee, S. S., Tsai, C. H., Ho, Y. C., Yu, C. C., Chang, Y. C. (2012a) Heat shock protein 27 expression in areca quid chewing-associated oral squamous cell carcinomas. Oral Dis. 18, 713–719. <>
56. Lee, S. S., Tsai, C. H., Tsai, L. L., Chou, M. C., Chou, M. Y., Chang, Y. C. (2012b) β-catenin expression in areca quid chewing associated oral squamous cell carcinomas and up-regulated by arecoline in human oral epithelial cells. J. Formos. Med. Assoc. 111, 194–200. <>
57. Lee, S. S., Tsai, C. H., Yu, C. C., Chang, Y. C. (2013) Elevated snail expression mediates tumor progression in areca quid chewing-associated oral squamous cell carcinoma via reactive oxygen species. PLoS One 8, e67985. <>
58. Lee, S. S., Chen, Y. J., Tsai, C. H., Huang, F. M., Chang, Y. C. (2015) Elevated transglutaminase-2 expression mediates fibrosis in areca quid chewing-associated oral submucocal fibrosis via reactive oxygen species generation. Clin. Oral Investig. 20, 1029–1034. <>
59. Lee, Y. H., Yang, L. C., Hu, F. W., Peng, C. Y., Yu, C. H., Yu, C. C. (2016) Elevation of Twist expression by arecoline contributes to the pathogenesis of oral submucous fibrosis. J. Formos. Med. Assoc. 115, 311–317. <>
60. Lin, C. H., Yu, M. C., Tung, W. H., Chen, T. T., Yu, C. C., Weng, C. M., Tsai, Y. J., Bai, K. J., Hong, C. Y., Chien, M. H., Chen, B. C. (2013) Connective tissue growth factor induces collagen I expression in human lung fibroblasts through the Rac1/MLK3/JNK/AP-1 pathway. Biochim. Biophys. Acta 1833, 2823–2833. <>
61. Lin, K. H., Lin, C. Y., Liu, C. C., Chou, M. Y., Lin, J. K. (2011) Arecoline N-oxide: Its mutagenicity and possible role as ultimate carcinogen in areca oral carcinogenesis. J. Agric. Food Chem. 59(7), 3420–3428. <>
62. Lin, W. T., Shieh, T. M., Yang, L. C., Wang, T. Y., Chou, M. Y., Yu, C. C. (2015) Elevated Lin28B expression is correlated with lymph node metastasis in oral squamous cell carcinomas. J. Oral Pathol. Med. 44, 823–830. <>
63. Liou, G. Y., Storz, P. (2010) Reactive oxygen species in cancer. Free Radic. Res. 44(5), 479–496. <>
64. Liu, F., Millar, S. E. (2010) Wnt/β-catenin signaling in oral tissue development and disease. J. Dent. Res. 89, 318–330. <>
65. Liu, S. Y., Liu, Y. C., Huang, W. T., Huang, G. C., Chen, T. C., Lin, M. H. (2007) Up-regulation of matrix metalloproteinase-8 by betel quid extract and arecoline and its role in 2D motility. Oral Oncol. 43, 1026–1033. <>
66. Lu, S. L., Reh, D., Li, A. G., Woods, J., Corless, C. L., Martin, M. K., Wang, X. J. (2004) Overexpression of transforming growth factor-1 in head and neck epithelia results in inflammation, angiogenesis, and epithelial hyperproliferation. Cancer Res. 64, 4405–4410. <>
67. Marchei, E., Durgbanshi, A., Rossi, S., Garcia-Algar, O., Zuccaro, P., Pichini, S. (2005) Determination of arecoline (areca nut alkaloid) and nicotine in hair by high-performance liquid chromatography/electrospray quadrupole mass spectrometry. Rapid Commun. Mass Spectrom. 19, 3416–3418. <>
68. McMohan, S., Charbonneau, M., Grandmont, S., Richard, D. E., Dubois, C. M. (2006) Transforming growth factor β1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression. J. Biol. Chem. 281(34), 24171–24181. <>
69. Micallef, L., Vedrenne, N., Billet, F., Coulomb, B., Darby, I. A., Desmoulière, A. (2012) The myofibroblast, multiple origins for major roles in normal and pathological tissue repair. Fibrogenesis Tissue Repair 5, S5. <>
70. Miyazaki, M., Sugawara, E., Yoshimura, T., Yamazaki, H., Kamataki, T. (2005) Mutagenic activation of betel quid-specific N-nitrosamines catalyzed by human cytochrome P450 coexpressed with NADPH-cytochrome P450 reductase in Salmonella typhimurium YG7108. Mutat. Res. 581(1–2), 165–171. <>
71. Montellano, P. R. O. (2013) Cytochrome P-450-activated prodrugs. Future Med. Chem. 5(2), 213–228. <>
72. Moutasim, K. A., Jenei, V., Sapienza, K., Marsh, D., Weinreb, P. H., Violette, S. M., Lewis, M. P., Marshall, J. F., Fortune, F., Tilakratne, W. M., Hart, I. R., Thomas, G. J. (2011) Betel-derived alkaloid up-regulates keratinocyte alphavbeta6 integrin expression and promotes oral submucous fibrosis. J. Pathol. 223, 366–377. <>
73. Nery, R. (1971) The metabolic interconversion of arecoline and arecoline 1-oxide in the rat. Biochem. J. 122(4), 503–508. <>
74. Nishikawa, A., Prokopczyk, B., Rivenson, A., Zang, E., Hoffmann, D. (1992) A study of betel quid carcinogenesis. VIII. Carcinogenicity of 3-(methylnitrosamino)propionaldehyde in F344 rats. Carcinogenesis 13(3), 369–372. <>
75. Ohshima, H., Friesen, M., Bartsch, H. (1989) Identification in rats of N-nitrosonipecotic acid as a major urinary metabolite of the areca-nut alkaloid-derived nitrosamines, N-nitrosoguvacoline and N-nitrosoguvacine. Cancer Lett. 44(3), 211–216. <>
76. Panigrahi, G. B., Rao, A. R. (1984) Induction of in vivo sister chromatid exchanges byarecaidine, a betel nut alkaloid, in mouse bone marrow cells. Cancer Lett. 23(2), 189–192. <>
77. Parker, C., Rampaul, R. S., Pinder, S. E., Bell, J. A., Wencyk, P. M., Blamey, R. W., Nicholson, R. I., Robertson, J. F. R., Ellis, I. O. (2001) E-cadherin as a prognostic indicator in primary breast cancer. Br. J. Cancer 85, 1958–1963. <>
78. Patterson, T. A., Kosh, J. W. (1993) Elucidation of the rapid in vivo metabolism of arecoline. Gen. Pharmacol. 24(3), 641–647. <>
79. Pellegrini, M., Marchei, E., Rossi, S., Vagnarelli, F., Durgbanshi, A., Garcia-Algar, O., Vall, O., Pichini, S. (2007) Liquid chromatography/electrospray ionization tandem mass spectrometry assay for determination of nicotine and metabolites, caffeine and arecoline in breast milk. Rapid Commun. Mass Spectrom. 21, 2693–2703. <>
80. Peng, W., Liu, Y. J., Wu, N., Sun, T., He, X. Y., Gao, Y. X., Wu, C. J. (2015) Areca catechu L. (Arecaceae): A review of its traditional uses, botany, phytochemistry, pharmacology and toxicology. J. Ethnopharmacol. 164, 340–356. <>
81. Pichini, S., Pellegrini, M., Pacifici, R., Marchei, E., Murillo, J., Puig, C., Vall, O., Garcia-Algar, O. (2003) Quantification of arecoline (areca nut alkaloid) in neonatal biological matrices by high-performance liquid chromatography/electrospray quadrupole mass spectrometry. Rapid Commun. Mass Spectrom. 17, 1958–1964. <>
82. Prokopczyk, B., Rivenson, A., Bertinato, P., Brunnemann, K. D., Hoffmann, D. (1987) 3-(Methylnitrosamino)proprionitrile: Occurrence in saliva of betel quid chewers, carcinogenicity, and DNA methylation in F344 rats. Cancer Res. 47(2), 467–471.
83. Prokopczyk, B., Bertinato, P., Hoffmann, D. (1988) Cyanoethylation of DNA in vivo by 3-(methylnitrosamino)propionitrile, an Areca-derived carcinogen. Cancer Res. 48(23), 6780–6784.
84. Rankin, E. B., Giaccia, A. J. (2016) Hypoxic control of metastasis. Science 352, 175–180. <>
85. Rehman, A., Ali, S., Lone, M. A., Atif, M., Hassona, Y., Prime, S. S., Pitiyage, G. N., James, E. L. N., Parkinson, E. K. (2016) Areca nut alkaloids induce irreparable DNA damage and senescence in fibroblasts and may create a favourable environment for tumour progression. J. Oral Pathol. Med. 45(5), 365–372. <>
86. Reichart, P. A., Philipsen, H. P. (2005) Oral erythroplakia – a review. Oral Oncol. 41, 551–561. <>
87. Richter, K., Kietzmann, T. (2016) Reactive oxygen species and fibrosis: further evidence of a significant liason. Cell Tissue Res. 365, 591–605. <>
88. Rivenson, A., Hoffmann, D., Prokopczyk, B., Amin, S., Hecht, S. S. (1988) Induction of lung and exocrine pancreas tumours in F344 rats by tobacco-specific and Areca-derived N-nitrosamines. Cancer Res. 48(23), 6912–6917.
89. Rivera, C. (2015) Essentials of oral cancer. Int. J. Clin. Exp. Pathol. 8, 11884–11894.
90. Samarakoon, R., Higgins, S. P., Higgins, C. E., Higgins, P. J. (2008) TGF-β1-induced plasminogen activator inhibitor-1 expression in vascular smooth muscle cells requires pp60(c-src)/EGFR(Y845) and Rho/ROCK signalling. J. Mol. Cell. Cardiol. 44, 527–538. <>
91. Shieh, D. H., Chiang, L. C., Lee, C. H., Yang, Y. H., Shieh, T. Y. (2004) Effects of arecoline, safrole, and nicotine on collagen phagocytosis by human buccal mucosal fibroblasts as a possible mechanism for oral submucous fibrosis in Taiwan. J. Oral Pathol. Med. 33, 581–587. <>
92. Shirname, L. P., Menon, M. M., Nair, J., Bhide, S. V. (1983) Correlation of mutagenicity and tumorigenicity of betel quid and its ingredients. Nutr. Cancer 5(2), 87–91. <>
93. Shirname, L. P., Menon, M. M., Bhide, S. V. (1984) Mutagenicity of betel quid and its ingredients using mammalian test systems. Carcinogenesis 5, 501–503. <>
94. Shivapurkar, N. M., D’Souza, A. V., Bhide, S. V. (1980) Effect of betel-quid chewing on nitrite levels in saliva. Food Cosmet. Toxicol. 18(3), 277–281. <>
95. Sun, L., Diamond, M. E., Ottaviano, A. J., Joseph, M. J., Ananthanarayan, V., Hidayatullah G., Munshi, H. G. (2008) Transforming growth factor-β1 promotes matrix metalloproteinase-9 mediated oral cancer invasion through snail expression. Mol. Cancer Res. 6(1), 10–20. <>
96. Sundqvist, K., Liu, Y., Nair, J., Bartsch, H., Arvidson, K., Grafström, R. C. (1989) Cytotoxic and genotoxic effects of areca nut-related compound in cultured human buccal epithelial cells. Cancer Res. 49, 5294–5298.
97. Thangjam, G. S., Kondaiah, P. (2009) Regulation of oxidative-stress responsive genes by arecoline in human keratinocytes. J. Periodontal Res. 44, 673–682. <>
98. Thangjam, G. S., Agarwal, P., Balapure, A. K., Rao, S. G., Kondaiah, P. (2009) Regulation of extracellular matrix genes by arecoline in primary gingival fibroblasts requires epithelial factors. J. Periodontal Res. 44, 736–743. <>
99. Tilakaratne, W. M., Klinikowski, M. F., Saku, T., Peters, T. J., Warnakuasuriya, S. (2006) Oral submucous fibrosis: review on aetiology and pathogenesis. Oral Oncol. 42, 561–568. <>
100. Topcu, Z., Chiba, I., Fujieda, M., Shibata, T., Ariyoshi, N., Yamazaki, H., Sevqican, F., Muthumala, M., Kobayashi, H., Kamataki, T. (2002) CYP2A6 gene deletion reduces oral cancer risk in betel quid chewers in Sri Lanka. Carcinogenesis 23(4), 595–598. <>
101. Tsai, C. C., Ma, R. H., Shieh, T. Y. (1999) Deficiency in collagen and fibronectin phagocytosis by human buccal mucosa fibroblasts in vitro as a possible mechanism for oral submucous fibrosis. J. Oral Pathol. Med. 28(2), 59–63. <>
102. Tsai, C. H., Chou, M. Y., Chang, Y. C. (2003) The up-regulation of cyclooxygenase-2 expression in human buccal mucosal fibroblasts by arecoline: A possible role in the pathogenesis of oral submucous fibrosis. J. Oral Pathol. Med. 32, 146–153. <>
103. Tsai, C. H., Yang, S. F., Chen, Y. J., Chou, M. Y., Chang, Y. C. (2005a) The upregulation of insulin-like growth factor-1 in oral submucous fibrosis. Oral Oncol. 41, 940–946. <>
104. Tsai, C. H., Yang, S. F., Chen, Y. J., Chou, M. Y., Chang, Y. C. (2005b) Raised keratinocyte growth factor-1 expression in oral submucous fibrosis in vivo and up-regulated by arecoline in human buccal mucosal fibroblasts in vitro. J. Oral Pathol. Med. 34, 100–105. <>
105. Tsai, C. H., Yang, S. F., Chang, Y. C. (2007) The upregulation of cystatin C in oral submucous fibrosis. Oral Oncol. 43, 680–685.
106. Tsai, C. H., Yang, S. F., Lee, S. S., Chang, Y. C. (2009) Augmented heme oxygenase-1 expression in areca quid chewing-associated oral submucous fibrosis. Oral Dis. 15, 281–286. <>
107. Tsai, C. H., Lee, S. S., Huang, F. M., Chang, Y. C. (2013) Regulation of protease-activated receptor-1 expression in human buccal fibroblasts stimulated with arecoline. Head Neck 35, 1314–1318. <>
108. Tsai, C. H., Lee, S. S., Chang, Y. C. (2015) Hypoxic regulation of plasminogen activator inhibitor-1 expression in human buccal mucosa fibroblasts stimulated with arecoline. J. Oral Pathol. Med. 44, 669–673. <>
109. Tsai, Y. P., Wu, K. J. (2012) Hypoxia-regulated target genes implicated in tumor metastasis. J. Biomed. Sci. 19, 102. <>
110. Tsai, Y. S., Lee, K. W., Huang, J. L., Liu, Y. S., Juo, S. H. H., Kuo, W. R., Chang, J. G., Lin, C. S., Jong, Y. J. (2008) Arecoline, a major alkaloid of areca nut, inhibits p53, represses DNA repair, and triggers DNA damage response in human epithelial cells. Toxicology 249, 230–237. <>
111. Wang, C. K., Peng, C. H. (1996) The mutagenicities of alkaloids and N-nitrosoguvacoline from betel quid. Mutat. Res. 360, 165–171. <>
112. Wang, T. S., Lin, C. P., Chen, Y. P., Chao, M. R., Li, C. C., Liu, K. L. (2018) CYP450-mediated mitochondrial ROS production involved in arecoline N-oxide-induced oxidative damage in liver cell lines. Environ. Toxicol. 33, 1029–1038. <>
113. Wang, Y. C., Tsai, Y. S., Huang, J. L., Lee, K. W., Kuo, C. C., Wang, C. S., Huang, A. M., Chang, J. Y., Jong, Y. J., Lin, C. S. (2010) Arecoline arrests cells at prometaphase by deregulating mitotic spindle assembly and spindle assembly checkpoint: Implication for carcinogenesis. Oral Oncol. 46, 255–262. <>
114. Wen, X. M., Zhang, Y. L., Liu, X. M., Guo, S. X., Wang, H. (2006) Immune responses in mice to arecoline mediated by lymphocyte muscarinic acetylcholine receptor. Cell Biol. Int. 30, 1048–1053. <>
115. Wenke, G., Hoffmann, D. (1983) A study of betel quid carcinogenesis. I. On the in vitro N-nitrosation of arecoline. Carcinogenesis 4(2), 169–172. <>
116. Wenke, G., Brunnemann, K. D., Hoffmann, D., Bhide, S. V. (1984a) A study of betel quid carcinogenesis. IV. Analysis of the saliva of betel chewers: a preliminary report. J. Cancer Res. Clin. Oncol. 108(1), 110–113. <>
117. Wenke, G., Rivenson, A., Hoffmann, D. (1984b) A study of betel quid carcinogenesis. 3. 3-(Methylnitrosamino)-propionitrile, a powerful carcinogen in F344 rats. Carcinogenesis 5(9), 1137–1140. <>
118. Wu, I. C., Chen, P. H., Wang, C. J., Wu, D. C., Tsai, S. M., Chao, M. R., Chen, B. H., Lee, H. H., Lee, C. H., Ko, Y. C. (2010) Quantification of blood betel quid alkaloids and urinary 8-hydroxydeoxyguanosine in humans and their association with betel chewing habits. J. Anal. Toxicol. 34, 325–331. <>
119. Yang, S. F., Hsieh, Y. S., Tsai, C. H., Chou, M. Y., Chang, Y. C. (2003) The upregulation of type I plasminogen activator inhibitor in oral submucous fibrosis. Oral Oncol. 39, 367–372. <>
120. Yang, S. F., Tsai, C. H., Chang, Y. C. (2008) The upregulation of heat shock protein 47 expression in human buccal fibroblasts stimulated with arecoline. J. Oral Pathol. Med. 37, 206–210. <>
121. Yang, W. H., Kuo, M. Y., Liu, C. M., Deng, Y. T., Chang, H. H., Chang, J. Z. (2013) Curcumin inhibits TGFβ1-induced CCN2 via Src, JNK, and Smad3 in gingiva. J. Dent. Res. 92, 629–634. <>
122. Yang, W. H., Deng, Y. T., Hsieh, Y. P., Wu, K. J., Kuo, M. Y. (2016) Thrombin activates latent TGFβ1 via integrin αvβ1 in gingival fibroblasts. J. Dent. Res. 95, 939–945. <>
123. Yu, C. C., Tsai, C. H., Hsu, H. I., Chang, Y. C. (2013) Elevation of S100A4 expression in buccal mucosal fibroblasts by arecoline: Involvement in the pathogenesis of oral submucous fibrosis. PLoS One 8, e55122. <>
124. Zhang, J., Cashman, J. R. (2006) Quantitative analysis of FMO gene mRNA levels in human tissues. Drug Metab. Dispos. 34, 19–26. <>
125. Zheng, L., Jian, X., Guo, F., Li, N., Jiang, C., Yin, P., Min, A. J., Huang, L. (2015) miR-203 inhibits arecoline-induced epithelial-mesenchymal transition by regulating secreted frizzled-related protein 4 and transmembrane-4 L six family member 1 in oral submucous fibrosis. Oncol. Rep. 33, 2753–2760. <>
126. Zhou, Z. S., Li, M., Gao, F., Peng, J. Y., Xiao, H. B., Dai, L. X., Lin, S. R., Zhang, R., Jin, L. Y. (2013) Arecoline suppresses HaCaT cell proliferation through cell cycle regulatory molecules. Oncol. Rep. 29, 2438–2444. <>
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