Areca nut alkaloids induce irreparable <scp>DNA</scp> damage and senescence in fibroblasts and may create a favourable environment for tumour progression

Rehman, Ambreen; Ali, Sitara; Lone, Mohid Abrar; Atif, Muhammad; Hassona, Yazan; Prime, Stephen S.; Pitiyage, Gayani; James, Emma L.; Parkinson, Eric Kenneth

doi:10.1111/jop.12370

Cited by 31 publications

(39 citation statements)

References 35 publications

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“…The [18]. This pleomorphic nature of culture may be due to the lack of natural defence and inherently irreversible DNA double-strand breaks [17,19].…”

Section: Discussionmentioning

confidence: 99%

Buccal Mucosal Epithelial Cells Downregulate CTGF Expression in Buccal Submucosal Fibrosis Fibroblasts

Gottipamula¹,

Sundarrajan²,

Moorthy³

et al. 2017

J. Maxillofac. Oral Surg.

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“…The [18]. This pleomorphic nature of culture may be due to the lack of natural defence and inherently irreversible DNA double-strand breaks [17,19].…”

Section: Discussionmentioning

confidence: 99%

Buccal Mucosal Epithelial Cells Downregulate CTGF Expression in Buccal Submucosal Fibrosis Fibroblasts

Gottipamula¹,

Sundarrajan²,

Moorthy³

et al. 2017

J. Maxillofac. Oral Surg.

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“…Arecoline was previously demonstrated to promote fibrosis in the oral submucosa and the progression to oral cancer (19). The majority of the other in vitro studies have used oral cancer-derived cells and immortalized cells to observe the effect of arecoline on oral epithelial cells, not primary cells (7,8).…”

Section: Discussionmentioning

confidence: 99%

Upregulated expression of MMP-9 in gingival epithelial cells induced by prolonged stimulation with arecoline

et al. 2017

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Abstract. Betel quid chewing is implicated in the high prevalence of oral cancer in Southeast Asian countries. One of the major components of betel quid is arecoline. In the present study, in order to characterize the association between chronic arecoline stimulation and carcinogenesis the expression level of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 mRNA in human gingival epithelial progenitor cells (HGEPs) stimulated with arecoline was assessed. The HGEPs were alternated between 3 days of incubation with arecoline (50 µg/ml), and 3 days without arecoline, for up to 30 days. The expression levels of the MMPs and TIMPs in the cells stimulated with arecoline were evaluated by reverse transcription-quantitative polymerase chain reaction at 18 and 30 days. The expression of MMP-9 mRNA in the experimental group was significantly increased compared with in the control group (P<0.01). No significant differences in the expression of MMP-2, TIMP-1 or TIMP-2 mRNA were observed between the experimental and control groups. Using an MMP-9 activity assay, the levels of MMP-9 activity in the experimental group were demonstrated to be significantly higher than in the control group (P<0.05). To investigate associated cellular signaling pathways, PDTC [a nuclear factor (NF)-κB/inhibitor of NF-κB (IκB) inhibitor], PD98059 [a mitogen-activated protein kinase kinase (MAPKK)1 and MAPKK2 inhibitor], SB203580 (a p38 MAPK inhibitor) and 5,15-DPP [a signal transduction and activator of transcription (STAT) 3 inhibitor] were used. All inhibitors decreased the extent of MMP-9 upregulation induced by stimulation with arecoline. Based on the data, it is hypothesized that MMP-9 activity may be involved in the pathological alterations of oral epithelium induced by betel quid chewing, and that the NF-κB/IκB, MAPK, p38 MAPK and STAT3 signaling pathways may be involved in the production of MMP-9 induced by betel quid chewing.

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“…Other areca nut components, such as flavonoids, catechins and tannins, facilitate the crosslinking of collagen fibers, resulting a decreased susceptibility to collagenase 29. Increases in transforming growth factor β1 (TGF-β1) during areca nut-induced oral submucosal fibrosis has also been observed in many studies 10, 23, 30. In the condition of submucous fibrosis, TGF-β plays a critical role in regulating the degradation of the extracellular matrix, including collagen 31.…”

Section: Molecular Pathology Of Areca Nutmentioning

confidence: 99%

Multifaceted Mechanisms of Areca Nuts in Oral Carcinogenesis: the Molecular Pathology from Precancerous Condition to Malignant Transformation

Li¹,

Cheng²,

Lee³

et al. 2019

J. Cancer

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Oral cancer is one of the most frequent malignant diseases worldwide, and areca nut is a primary carcinogen causing this cancer in Southeast Asia. It has been widely reported that areca nut induced several cytotoxic effects in oral cells, including ROS generation, inflammation, tissue hypoxia, DNA damage, and cell invasion. Recently, through chronic exposure model, more extensive pathological effects due to areca nut have been found. These include the induction of autophagy, promotion of epithelial-mesenchymal transition, and facilitation of cancer stemness conversion. Clinical findings support these adverse effects. Oral submucosal fibrosis, a premalignant condition, is prevalent in the area with habitual chewing of areca nuts. Consistently, oral cancer patients with habitual chewing areca nut exhibit more aggressive phenotypes, including resistance to chemo-radiotherapy. In this review, we comprehensively discuss and concisely summarize the up-to-date molecular and cellular mechanisms by which areca nuts contribute to malignant transformation. This review may provide critical information regarding clinical applications in risk assessment, disease prevention, diagnosis, and personalized therapeutics for areca nut-induced oral malignancy.

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Areca nut alkaloids induce irreparable DNA damage and senescence in fibroblasts and may create a favourable environment for tumour progression

Abstract: Areca nut alkaloids induce senescence in oral fibroblasts and promote increased secretion of TGF-β and perhaps MMP-2 that may create a tissue environment thought to be critical in the progression of OSMF to malignancy.

Cited by 31 publications

References 35 publications

Buccal Mucosal Epithelial Cells Downregulate CTGF Expression in Buccal Submucosal Fibrosis Fibroblasts

Buccal Mucosal Epithelial Cells Downregulate CTGF Expression in Buccal Submucosal Fibrosis Fibroblasts

Upregulated expression of MMP-9 in gingival epithelial cells induced by prolonged stimulation with arecoline

Multifaceted Mechanisms of Areca Nuts in Oral Carcinogenesis: the Molecular Pathology from Precancerous Condition to Malignant Transformation

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