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Review
. 2023 Feb 21;13(2):326-346.
doi: 10.3390/clinpract13020030.

Carcinogenic Effects of Areca Nut and Its Metabolites: A Review of the Experimental Evidence

Kalpani Senevirathna  1 , Roshan Pradeep  1 , Yovanthi Anurangi Jayasinghe  1 , Shalindu Malshan Jayawickrama  1 , Rasika Illeperuma  1 , Saman Warnakulasuriya  2 , Ruwan Duminda Jayasinghe  1   3
Affiliations
Review

Carcinogenic Effects of Areca Nut and Its Metabolites: A Review of the Experimental Evidence

Kalpani Senevirathna et al. Clin Pract. .

Abstract

Oral cancers (OC) are among the most frequent malignancies encountered in Southeast Asia, primarily due to the prevalent habit of betel quid (BQ) and smokeless tobacco use in this region. Areca nut (AN), the primary ingredient in BQ, contains several alkaloids, including arecoline, arecaidine, guvacoline, and guvacine. These have been associated with both the AN abuse liability and carcinogenicity. Additionally, variations in AN alkaloid levels could lead to differences in the addictiveness and carcinogenic potential across various AN-containing products. Recent studies based on animal models and in vitro experiments show cellular and molecular effects induced by AN. These comprise promoting epithelial-mesenchymal transition, autophagy initiation, tissue hypoxia, genotoxicity, cytotoxicity, and cell death. Further, clinical research endorses these undesired harmful effects in humans. Oral submucosal fibrosis, a potentially malignant disease of the oral cavity, is predominantly reported from the geographical areas of the globe where AN is habitually chewed. OC in chronic AN users presents a more aggressive phenotype, such as resistance to anti-cancer drugs. The available evidence on the carcinogenicity of AN based on the findings reported in the recently published experimental studies is discussed in the present review.

Keywords: areca nut; carcinogenicity; cytotoxicity; genotoxicity; in vivo and in vitro studies; oral cancer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Clinical conditions associated with Areca nut (AN) chewing: (A,B) Oral squamous cell carcinoma—OSCC, (C,D) Oral lichenoid reactions—OLL, (E,F) oral erythroplakia—OE, (G,H) oral leukoplakia—OL (I,J) Erythroleukoplakia, (K,L) Oral lichen planus—OLP.
Figure 2
Figure 2
Schematic representation of the action of reactive oxygen species (ROS) leading to inflammation. ADAM17 (ADAM metallopeptidase domain 17); ASC (Activating signal co-integrator 1); BMP4 (Bone morphogenetic protein 4); IKB-α (Inhibitor of nuclear factor kappa B kinase regulatory subunit alpha); IKK (Inhibitor of nuclear factor kappa-B kinase); IP3R (Inositol 1,4,5-trisphosphate receptor type 3); JNK (c-Jun N-terminal kinase); LPC (Lysophosphatidylcholine); LPS (Lipopolysaccharide); NF-κB (Nuclear factor kappa subunit B); NLRP3 (NLR family pyrin domain containing 3); NOX (NADPH oxidase); OxPL (Oxidized phospholipids); PAR (Par family cell polarity regulator); PAK (p21 (RAC1) activated kinase); SOD (Superoxide dismutase); TLR4 (Toll-like receptor 4); TNF-α (Tumor necrosis factor alpha); TNFR (TNF receptor superfamily); TNFR1 (TNF receptor superfamily 1); TXNIP (Thioredoxin interacting protein); Ub (Ubiquitin).
Figure 3
Figure 3
Molecular mechanisms regulating Epithelial-Mesenchymal Transition (EMT). During EMT, the epithelial cells are converted into mesenchymal-like cells. The reverse transition from mesenchymal to epithelial cells is known as a mesenchymal–epithelial transition (MET). CDH1 (Cadherin 1); DLL1/3/4 (Delta-like canonical Notch ligand 1); ECM (Extracellular matrix); EGF (Epidermal growth factor); EGFR (Epidermal growth factor receptor); EMT-TF (Epithelial-mesenchymal transition-transcription factors); GSK3β (Glycogen synthase kinase-3 beta); HIF-1α (Hypoxia-inducible factor-1); JAG2 (Hs00171432_m1), JAG1 (Hs01070032_m1); MAPK (Mitogen-activated protein kinase); MMPs (Matrix metalloproteinases); NICD (Notch Intracellular Domain); PI3K (Phosphatidylinositol 3 kinase); SMAD (Suppressor of Mothers against Decapentaplegic); SNAI1 (Zinc finger protein); STAT3 (Signal transducer and activator of transcription 3); TGF-β (Transforming growth factor-β); TWIST1 (Twist-related protein-1); WNT (Wingless/Integrated pathway); ZEB1/2 Zinc finger and homeodomain transcription factor.
Figure 4
Figure 4
The molecular pathway of Autophagy. Due to the microenvironmental stress, AMP-activated protein kinase (AMPK) is activated, leading to the activation of ULK-1 complex (ULK-1, ATG13, ATG101, and FIP200). ULK-1 complex activation leads the assembly of Class III Phosphoinositide 3-kinases (PI3Ks) (Beclin-1, Vps34, AMBRA, p150, and ATG14). Both ULK-1 complex and Class III PI3K translocate to the nucleation site and stimulate the establishment of the isolation membrane known as the phagophore. Elongation of the phagophore befalls via the effect of ATG5-ATG12-ATG16 and LC3-II until a double membrane vesicle is formed, known as the autophagosome. Autophagosomes fuse with the lysosome, which leads to degradation of cargo via the effect of lysosomal enzymes with release of biomolecules.
Figure 5
Figure 5
Activation and degradation of the hypoxia-inducible factor-1α (HIF-1α). In normoxia, HIF-1α is degraded rapidly, while in hypoxic conditions, it is accumulated. HIF-1α associates with HIF-1β, and the resulting heterodimer binds to the hypoxia response element (HRE) of target genes. The factor inhibiting HIF-1 (FIH-1) is a protein that binds to HIF-1α and inhibits its transactivation function. The von Hippel–Lindau (VHL) protein is a tumor suppressor.
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