Novel Pathways and Mechanism of Nicotine-Induced Oral Carcinogenesis

Background: Smokeless Tobacco (SLT) contains 9 times more nicotine than Smoked Tobacco (SMT). The carcinogenic effect of nicotine is intensified by converting nicotine-to-nicotine-derived Nitrosamines (NDNs). Methods: A review of the literature was conducted with a tailored search strategy to unravel the novel pathways and mechanisms of nicotine-induced oral carcinogenesis. Results: Nicotine and NDNs act on nicotinic Acetylcholine Receptors (nAChRs) as agonists. Nicotine facilitates cravings through α4β2nAChR and α7nAChR, via enhanced brain dopamine release. Nicotine binding to nAChR promotes proliferation, migration, invasion, chemoresistance, radioresistance, and metastasis of oral cancer cells. Nicotine binding to α7nAChR on keratinocytes triggers Ras/Raf-1/MEK1/ERK cascade promoting anti-apoptosis and pro-proliferative effects. Furthermore, the nicotine-enhanced metastasis is subdued on nAChR blockade through reduced nuclear localization of p-EGFR. Conclusion: Protracted exposure to nicotine/NDN augments cancer-stimulatory α7nAChR and desensitizes cancer inhibitory α4β2nAChR. Since nAChRs dictate both addictive and carcinogenic effects of nicotine, it seems counterintuitive to designate nicotine just as an addictive agent devoid of any carcinogenicity.

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Alanine-Scanning Mutagenesis of α-Conotoxin GI Reveals the Residues Crucial for Activity at the Muscle Acetylcholine Receptor

Marine Drugs ◽

10.3390/md16120507 ◽

2018 ◽

Vol 16 (12) ◽

pp. 507 ◽

Cited By ~ 7

Author(s):

Jiong Ning ◽

Rui Li ◽

Jie Ren ◽

Dongting Zhangsun ◽

Xiaopeng Zhu ◽

...

Keyword(s):

Nicotinic Acetylcholine Receptors ◽

Acetylcholine Receptors ◽

The Novel ◽

Muscle Type ◽

Alanine Scanning Mutagenesis ◽

Dynamic Simulations ◽

Alanine Scanning ◽

Critical Residue ◽

Hydrophobic Amino Acids ◽

Critical Residues

Recently, the muscle-type nicotinic acetylcholine receptors (nAChRs) have been pursued as a potential target of several diseases, including myogenic disorders, muscle dystrophies and myasthenia gravis, etc. α-conotoxin GI isolated from Conus geographus selectively and potently inhibited the muscle-type nAChRs which can be developed as a tool to study them. Herein, alanine scanning mutagenesis was used to reveal the structure–activity relationship (SAR) between GI and mouse α1β1δε nAChRs. The Pro5, Gly8, Arg9, and Tyr11 were proved to be the critical residues for receptor inhibiting as the alanine (Ala) replacement led to a significant potency loss on mouse α1β1δε nAChR. On the contrary, substituting Asn4, His10 and Ser12 with Ala respectively did not affect its activity. Interestingly, the [E1A] GI analogue exhibited a three-fold potency for mouse α1β1δε nAChR, whereas it obviously decreased potency at rat α9α10 nAChR compared to wildtype GI. Molecular dynamic simulations also suggest that loop2 of GI significantly affects the interaction with α1β1δε nAChR, and Tyr11 of GI is a critical residue binding with three hydrophobic amino acids of the δ subunit, including Leu93, Tyr95 and Leu103. Our research elucidates the interaction of GI and mouse α1β1δε nAChR in detail that will help to develop the novel analogues of GI.

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Cytogenetic alterations induced by flupyradifurone, a new butenolide insecticide, in human lymphocytes

Toxicology and Industrial Health ◽

10.1177/0748233718788989 ◽

2018 ◽

Vol 34 (11) ◽

pp. 737-743 ◽

Cited By ~ 2

Author(s):

Zülal Atlı Şekeroğlu ◽

Adem Aydın ◽

Seval Kontaş Yedier ◽

Vedat Şekeroğlu

Keyword(s):

Nicotinic Acetylcholine Receptors ◽

Acetylcholine Receptors ◽

Human Lymphocytes ◽

Metabolic Activation ◽

Genotoxic Effects ◽

New Class ◽

Lymphocyte Cultures ◽

Solvent Control ◽

Carcinogenic Effects ◽

Nuclear Division Index

Flupyradifurone (FPD), a member of the new class of butenolide insecticides, acts on nicotinic acetylcholine receptors. Studies on genotoxic and carcinogenic effects of FPD are very limited. This is the first study to investigate the cytotoxic and genotoxic effects of FPD and its metabolites on human lymphocyte cultures with or without a metabolic activation system (S9 mix) using chromosomal aberration (CA) and micronucleus (MN) tests. The cultures were treated with 85, 170, and 340 µg/ml of FPD in the presence (3 h treatment) and absence (48 h treatment) of S9 mix. Dimethyl sulfoxide (DMSO) was used as a solvent control. Statistically significant decreases were detected at the medium and highest concentrations for 48 h treatments while decreases in mitotic index (MI) in the presence of the S9 mix were found statistically significant at all FPD concentrations tested when compared with the solvent control. FPD also decreased the nuclear division index (NDI) at the highest concentration (340 µg/ml) in the absence of S9 mix. When compared with the solvent control, increases in CA frequencies were significant at the medium and highest concentrations. Significantly increased MN frequency was only found at the highest FPD concentration in cultures without S9 mix compared with the solvent control while increases in the MN frequencies in the presence of S9 mix were statistically significant at all FPD concentrations. The results of the present study indicate that FPD and its metabolites can show cytotoxic and genotoxic effects in human lymphocytes. More genotoxicity studies are necessary to make a possible risk assessment in humans.

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