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NNK, a nitrosated derivative of nicotine, concurrently induces phosphorylation of Bcl2 uniquely at Ser70 and c-Myc at Thr58 and Ser62 via activation of both ERK1/2 and PKCα[1]. NNK promotes the survival and proliferation of human lung cancer cells and can be utilized in constructing lung cancer mouse models[2].
体外研究
NNK (100 pM; 0-60 min) triggers the activation of PKCα and MAPKs ERK1/2, which directly leads to c-Myc phosphorylation[1].
NNK (100 pM; 96 hours) boosts the proliferation of cells expressing wild-type (WT) but not the AA mutant of c-Myc[1].
NNK 细胞实验
Cell Line
Concentration
Treated Time
Description
References
MLE-12 cells
10 µM
24 hours
NNK significantly increased AGT protein expression.
NNK upregulated CD36 expression and promoted cell proliferation, migration, and invasion.
iScience. 2023 Jul 27;26(8):107477
Bet1A
10 mM
12 hours
NNK upregulated CD36 expression and promoted cell proliferation, migration, and invasion.
iScience. 2023 Jul 27;26(8):107477
NCI-H23
10 mM
12 hours
NNK upregulated CD36 expression and promoted cell proliferation, migration, and invasion.
iScience. 2023 Jul 27;26(8):107477
Alveolar type II cells
0.1 µM and 1.2 µM
180 minutes
To study the metabolism of NNK in the lung and the distribution of its metabolites, it was found that NNK is metabolized in the lung primarily through detoxification pathways, with approximately 55% of metabolites formed through detoxification pathways and roughly 30% through bioactivation pathways.
Drug Metab Dispos. 2010 May;38(5):752-60
HBEL/p53i cells
10 µM
2 weeks
NNK significantly increased foci formation, which was significantly abrogated by treatment with an ACE inhibitor or AGTR1 antagonist.
Exp Mol Med. 2023 Jun;55(6):1131-1144
BEAS-2B cells
10 µM
24 hours
NNK induced AGT expression and secretion of AngII, leading to the acquisition of transformed phenotypes in lung epithelial cells.
Exp Mol Med. 2023 Jun;55(6):1131-1144
H1299
10 µM
24 hours
NNK increased DNMT1 protein levels and resulted in hypermethylation of TSG promoters
J Clin Invest. 2010 Feb;120(2):521-32
A549
10 µM
24 hours
NNK increased DNMT1 protein levels and resulted in hypermethylation of TSG promoters
J Clin Invest. 2010 Feb;120(2):521-32
IMR90
10 µM
24 hours
NNK increased DNMT1 protein levels and resulted in hypermethylation of TSG promoters
J Clin Invest. 2010 Feb;120(2):521-32
BEAS-2B cells
50, 100, 200 mg/L
24 hours
To detect the expression level of RRM2-C2orf48 in BEAS-2B cells after NNK treatment, results showed that 200 mg/L dose significantly upregulated RRM2-C2orf48 expression
iScience. 2022 Dec 2;26(1):105708
BEAS-2B cells
50, 100, 200, 400 mg/L
24 hours
To assess the effect of NNK on the viability of BEAS-2B cells, results showed that NNK reduced cell viability in a dose-dependent manner
iScience. 2022 Dec 2;26(1):105708
H1299 cells
100 pM
24 hours
NNK significantly enhances migration and invasion of H1299 cells and accelerates wound healing.
Cancer Lett. 2012 May 1;318(1):106-13
B-Vector cells
265.04 µM
24 hours
Evaluate the cytotoxicity of NNK in B-Vector cells, results showed B-Vector cells were moderately sensitive to NNK
Molecules. 2022 Jul 29;27(15):4851
B-2A13 cells
24.52 µM
24 hours
Evaluate the cytotoxicity of NNK in B-2A13 cells, results showed B-2A13 cells were more sensitive to NNK
Molecules. 2022 Jul 29;27(15):4851
BEAS-2B cells
376.14 µM
24 hours
Evaluate the cytotoxicity of NNK in BEAS-2B cells, results showed BEAS-2B cells were less sensitive to NNK
Molecules. 2022 Jul 29;27(15):4851
FaDu (human hypopharyngeal squamous cancer cells)
1 µM and 2 µM
24 hours
To investigate the effect of NNK on MSH2 and MLH1 protein and mRNA expression in FaDu cells. Results showed that NNK significantly upregulated miR-21 and miR-155, downregulated miR-422a, and reduced MSH2 and MLH1 protein and mRNA expression. Inhibition of miR-21 restored NNK-induced reduction in MSH2 expression.
Cells. 2020 Apr 21;9(4):1031
NCI-H1703 (human lung squamous cancer cells)
1 µM and 2 µM
24 hours
To investigate the effect of NNK on MSH2 and MLH1 protein and mRNA expression in NCI-H1703 cells. Results showed that NNK significantly upregulated miR-21 and miR-155, downregulated miR-422a, and reduced MSH2 and MLH1 protein and mRNA expression. Inhibition of miR-21 restored NNK-induced reduction in MSH2 expression.
Cells. 2020 Apr 21;9(4):1031
Het-1A cells
1 µM
24 hours
NNK stimulated expression of oncogenic genes, including ETS1, NRAS and SRC, which could be abolished in the presence of rSLURP-1.
Life Sci. 2012 Nov 27;91(21-22):1122-5
BEP2D cells
1 µM
24 hours
NNK stimulated expression of oncogenic genes, including MYB and PIK3CA, which could be abolished in the presence of rSLURP-1.
Life Sci. 2012 Nov 27;91(21-22):1122-5
MRC-5 cells
10 µM
24, 48, and 72 hours
NNK treatment significantly reduced GRα mRNA and protein expression levels and caused accumulation of DNMT1 at GR promoters 1B and 1F
Sci Rep. 2018 Mar 20;8(1):4903
Panc-1
1 µM
24-48 hours
NNK significantly enhanced the colony formation ability and spherogenesis of pancreatic cancer cells, while increasing the expression levels of stem cell markers OCT-4, SOX-2, and Nanog.
Mol Oncol. 2022 Aug;16(15):2881-2895
BxPC-3
1 µM
24-48 hours
NNK significantly enhanced the colony formation ability and spherogenesis of pancreatic cancer cells, while increasing the expression levels of stem cell markers OCT-4, SOX-2, and Nanog.
Mol Oncol. 2022 Aug;16(15):2881-2895
NCI-H23 cells
10 µM
28 days
To study the role of TCTP in NNK-induced EMT, results showed up-regulation of TCTP and vimentin expression
J Transl Med. 2020 Feb 11;18(1):66
Bet1A cells
10 µM
28 days
To study the role of TCTP in NNK-induced EMT, results showed up-regulation of TCTP and vimentin expression
J Transl Med. 2020 Feb 11;18(1):66
Beas-2B
10 µM
6 hours
DNMT1 protein returned to basal levels 2–6 hours after discontinuation of NNK treatment
J Clin Invest. 2010 Feb;120(2):521-32
LLC
25 µM
72 hours
NNK significantly upregulated IDO1 expression but did not affect IDO2, TDO, or TPH1 expression.
Signal Transduct Target Ther. 2022 Sep 7;7(1):311
EPLC-32M
25 µM
72 hours
NNK significantly upregulated IDO1 expression but did not affect IDO2, TDO, or TPH1 expression.
Signal Transduct Target Ther. 2022 Sep 7;7(1):311
A549
25 µM
72 hours
NNK significantly upregulated IDO1 expression but did not affect IDO2, TDO, or TPH1 expression.
Signal Transduct Target Ther. 2022 Sep 7;7(1):311
16HBE
25 µM
72 hours
NNK significantly upregulated IDO1 expression but did not affect IDO2, TDO, or TPH1 expression.
Signal Transduct Target Ther. 2022 Sep 7;7(1):311
CAL-27 cells
5 µM
96 hours
NNK stimulates DEPDC1 expression by promoting the methylation of its gene body through increased DNMT1 expression in OSCC cells.
Am J Cancer Res. 2020 Jun 1;10(6):1745-1760
HSC-3 cells
5 µM
96 hours
NNK stimulates DEPDC1 expression by promoting the methylation of its gene body through increased DNMT1 expression in OSCC cells.
Am J Cancer Res. 2020 Jun 1;10(6):1745-1760
2B-NNK cells
100 mg/L
multiple exposures
To evaluate the effect of RRM2-C2orf48 overexpression on NNK-induced malignant transformation of BEAS-2B cells, results showed that RRM2-C2orf48 overexpression accelerated malignant transformation
iScience. 2022 Dec 2;26(1):105708
NNK 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Fischer 344 rats
Isolated perfused rat lung (IPRL) model
Perfusion
0.1 μM and 1.2 μM
Single perfusion, lasting 180 minutes
To study the metabolism of NNK in the lung and the formation of DNA adducts, it was found that NNK is metabolized in the lung primarily through detoxification pathways, with approximately 55% of metabolites formed through detoxification pathways and roughly 30% through bioactivation pathways. The addition of PEITC significantly reduced the formation of oxidative metabolites and increased the formation of NNAL and the percentage of unmetabolized NNK. PEITC also significantly decreased the formation of DNA adducts in the lung tissue.
Drug Metab Dispos. 2010 May;38(5):752-60
Mice
NNK-induced lung cancer model and K-rasLA1 transgenic mice
Intravenous injection
10 μM
Once a week for 13 weeks (NNK model) or 5 weeks (K-rasLA1 model)
MiR-124 agomiR significantly suppressed NNK-induced and K-ras mutation-driven lung tumorigenesis
Mol Ther Nucleic Acids. 2017 Dec 15;9:145-154
A/J mice
NNK-induced lung adenocarcinoma model
Intraperitoneal injection
100 mg/kg
Every other day, three times, lasting for 16 weeks
NNK promoted lung adenocarcinoma development through CD36.
iScience. 2023 Jul 27;26(8):107477
A/J mice
A/J mice
Intraperitoneal injection
100 mg/kg
Single injection
To evaluate the protective effect of HB diet against NNK-induced lung tumorigenesis, results showed HB downregulated cyp2a4 and cyp2a5 mRNA expression and facilitated the formation of non-carcinogenic NNK metabolites
Pharmaceuticals (Basel). 2024 Nov 30;17(12):1615
Mice
Pten +/− mice
Intraperitoneal injection
100 mg/kg
Single dose or three doses weekly, lasting 16-24 weeks
To evaluate the effect of NNK on lung tumorigenesis in Pten +/? mice. Results showed that in lung tumor-susceptible pseudo–A/J mice, NNK treatment led to increased lung tumor size in Pten +/? mice but did not increase tumor multiplicity. In lung tumor-resistant C57BL/6 mice, NNK treatment did not induce lung tumors.
Neoplasia. 2008 Aug;10(8):866-72
A/J and C3H mice
Lung tumor model
Intraperitoneal injection
100 mg/kg/day
Every other day for three doses
To study the effect of NNK on lung tumorigenesis in A/J and C3H mice. Results showed that NNK induced lung tumors in A/J mice but not in C3H mice.
Am J Respir Cell Mol Biol. 2007 Jan;36(1):13-9
A/J mice
Lung adenoma model
Intraperitoneal injection
2 mg
Single injection, terminated 24 weeks after treatment
NNK induced increased expression levels of DNMT1, p-AKTser473, p-GSK3βser9, cytoplasmic hnRNP-U, and cytoplasmic βTrCP proteins
J Clin Invest. 2010 Feb;120(2):521-32
Mice
Agt+/+ and Agt+/- mice
Oral gavage
3 μmol
Twice a week for 20 weeks
NNK significantly increased the multiplicity, volume, and load of lung tumor nodules, and these changes were significantly suppressed in Agt+/- mice.
Exp Mol Med. 2023 Jun;55(6):1131-1144
A/J mice
NNK-induced lung cancer model
Injection
50 mg/kg
Twice, one week apart, for 20 weeks
To compare the efficacy of different fat types in ketogenic diets in preventing NNK-induced lung cancer. Results showed that the fish oil-enriched ketogenic diet (FO-KD) was most effective in reducing lung nodule numbers.
Sci Rep. 2024 Mar 7;14(1):5610
A/J mice
Lung cancer model
Gavage
50 mg/kg
Twice a week for 5 weeks
NNK significantly upregulated IDO1 expression in lung tissues and reduced CD8+T cells while increasing Tregs.
Signal Transduct Target Ther. 2022 Sep 7;7(1):311
Ferrets (Mustela putorius furo)
Human lung cancer model
Intraperitoneal injection
50 mg/kg
Once a month for four consecutive months, followed by observation for 24, 26, and 32 weeks
To investigate whether NNK exposure alone induces both preneoplastic and neoplastic lesions in ferret lungs. Results showed that NNK exposure led to preneoplastic lesions (squamous metaplasia, dysplasia, and atypical adenomatous hyperplasia) and tumors (squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma) in ferret lungs, with tumor incidence being time-dependent (16.7%, 40.0%, and 66.7% at 24, 26, and 32 weeks, respectively). Additionally, NNK exposure significantly increased α7 nAChR protein expression and showed a tendency for increased phospho-ERK and cyclin D1 protein levels.
Lung Cancer. 2013 Dec;82(3):390-6
A/J mice
NNK-induced lung cancer model
Intraperitoneal injection
50 mg/kg
Two injections, one week apart, for 20 weeks
To investigate the inhibitory effect of soy saponins and isoflavones on NNK-induced lung nodule formation. Results showed that the combination of soy saponins and isoflavones significantly reduced the number of lung nodules and increased plasma isoflavone levels.
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