ライフサイエンスコーパス: NNK

1 NNK also stimulates activation of c-Src, which is a know

2 NNK and NNAL can induce lung cancer in laboratory animal

3 NNK and NNN are metabolized to DNA-reactive species that

4 NNK cannot only induce DNA damage but also promotes the

5 NNK had no significant effect on any of these measuremen

6 NNK induces voltage-dependent calcium channel (VDCC)-int

7 NNK is extensively metabolized to its carbonyl reduction

8 NNK is metabolically activated to intermediates that met

9 NNK is metabolically activated to methylating and pyridy

10 NNK may thus act as a site-of-entry carcinogen.

11 NNK significantly contributes to smoking-related lung ca

12 NNK treatment caused the development of lung tumors in a

13 NNK was administered s.c. at a dose of 1.5 mg/kg body we

14 NNK was detected in the treated wastewater before the FP

15 In group 1 (NNK plus HF diet), adenomas, adenocarcinomas, and adenos

16 rades 2, 3, and 4, respectively; in group 2 (NNK plus LF diet), the corresponding mean grades were 1,

17 d (BEAS-2B), carcinogen-transformed (BEAS-2B(NNK)), and RA-chemoprevented (BEAS-2B(NNK/RA)) HBE cells

18 EAS-2B(NNK)), and RA-chemoprevented (BEAS-2B(NNK/RA)) HBE cells were used to conduct microarray analy

19 cases (versus 6% of the controls) had >or=5 NNK-induced micronuclei, 89% of cases (and no controls)

20 d m-calpain may act as required targets in a NNK-induced metastatic signaling pathway.

21 During absorption, NNK was distributed within the entire depth of the mucos

22 Coexpression of beta1AR and ERbeta activated NNK-mediated ERK1/2 cooperatively.

23 rough the drinking water starting 24 h after NNK treatment significantly inhibited NNK-induced early

24 pose that CC10 has a protective role against NNK-induced lung tumorigenesis mediated via down-regulat

25 ndings reveal a novel role for PKCiota as an NNK-activated physiological Bad kinase that can directly

26 Redundant Akt activation by nicotine and NNK could contribute to tobacco-related carcinogenesis b

27 bound to STAT3 and responded to nicotine and NNK stimulation.

28 Spontaneous and NNK-induced chromosomal damage were significantly higher

29 sing the 95th percentiles of spontaneous and NNK-induced micronuclei, nucleoplasmic bridges, and nucl

30 ngs suggest a role for the ERK1/2 kinases as NNK-activated physiological calpain kinases.

31 nduced by PAHs and other carcinogens such as NNK.

32 Because NNK-induced lung tumors arise from the Type II cells, th

33 Because NNK-induced tumors arise from Type II cells, these resul

34 50 enzyme isoform (CYP2A5) that bioactivates NNK into mutagenic metabolites.

35 or a Src-specific inhibitor (PP2) can block NNK-induced Bad phosphorylation and promote apoptotic ce

36 lpain expression by RNA interference blocked NNK-stimulated migration and invasion, suggesting that m

37 ards G(1)/S cell cycle transition and blocks NNK-induced cell proliferation.

38 c receptor inhibitor propranolol blocks both NNK-induced activation of PKCiota and Bad phosphorylatio

39 n was observed at similar prevalence in both NNK-induced hyperplasias and adenocarcinomas (46% versus

40 of PKCiota by RNA interference inhibits both NNK-induced Bad phosphorylation and survival, this confi

41 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) (0.05 ng/L) and 4-(methylnitrosamino)-1-(3-pyridyl)

42 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (

43 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (BaP) in A/J mice.

44 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) can undergo metabol

45 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosonicotine (NNN) are potent carcinogens

46 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and vinyl carbamate (VC) during mouse lung carcinog

47 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and vinyl carbamate, and the occupational carcinoge

48 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by measuring the frequency of NNK-induced chromosom

49 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by s.c. injection at a dose of 1.5 mg/kg body weigh

50 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) given by gavage once weekly for 8 weeks.

51 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in a 2-year bioassay.

52 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in male F344 rats that had been fed either a semipu

53 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in people who had stopped smoking: 4-(methylnitrosa

54 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces Ca(2+) signalling, a mechanism that is impl

55 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) into DNA-altering compounds that cause lung cancer.

56 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is an important component in cigarette smoke and is

57 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is formed by nitrosation of nicotine and has been i

58 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is formed by nitrosation of nicotine and has been i

59 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is of particular interest due to its potency and it

60 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is the most potent carcinogen contained in cigarett

61 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) or vinyl carbamate (VC) resulted in a significant o

62 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) reproducibly induces pulmonary adenocarcinomas (ACs

63 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were previously shown to be highly persistent in hu

64 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) within DNA duplexes representing p53 mutational "ho

65 methylnitrosamino)-I-(3-pyridyl)-1-butanone (NNK), 4ebp1(-/-)/4ebp2(-/-) mice showed increased sensit

66 Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific lung carcinogen, is believed to

67 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol

68 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and its inhibition by black tea have been characte

69 methylnitrosamino)-1-(3 pyridyl)-1-butanone (NNK), BEAS-2B cells exhibited evidence of transformation

70 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), have not been elucidated.

71 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in the canine trachea.

72 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is a chemical carcinogen thought to be involved in

73 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), O(6)-methyl-dG (O(6)-Me-dG) and O(6)-pyridyloxobut

74 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), selectively induces lung tumors in F344 rats.

75 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung cancer by producing carcinogenic metab

76 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumor progression from adenoma to aden

77 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis.

78 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

79 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

80 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

81 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

82 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

83 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

84 ethylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK).

85 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

86 methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK); and r-1-,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydro

87 methylnitrosamino)-1-(3-pyridyl)-1-butanone, NNK, a potent carcinogen in tobacco smoke.

88 as and Raf, reduced stimulation of ERK1/2 by NNK.

89 1 (ERK1) and p42 MAPK/ERK2 were activated by NNK, co-localized with mu- and m-calpain in cytoplasm, a

90 lso reduced liver tumor incidence induced by NNK from 34% in the group given only deionized water to

91 P < 0.001) was observed in tumors induced by NNK.

92 th the development of lung tumors induced by NNK.

93 inhibition of lung tumorigenesis induced by NNK.

94 ression in response to DNA damage induced by NNK.

95 derstanding mechanisms of tumor induction by NNK.

96 e in lung cancer induced in the A/J mouse by NNK.

97 itor of lung tumor induction in F344 rats by NNK, on O6-methyldeoxyguanosine (O6-mG) and pyridyloxobu

98 The BEAS-2B cells transformed by NNK exhibited an increase in cyclin E expression which w

99 NHBE cells exposed to the tobacco carcinogen NNK.

100 K bioavailability, consistent with decreased NNK bioactivation in the lung.

101 ystemic clearance of NNK, thereby decreasing NNK-induced lung cancer.

102 in the same region where the second, distal NNK molecule is bound, suggesting that the channel may b

103 ated signature proteins are increased during NNK plus BaP-induced lung carcinogenesis, and I3C inhibi

104 ERbeta enhanced NNK-induced cyclic AMP accumulation as well as Galphai-m

105 ike N2-guanine adducts of PAH diol epoxides, NNK-induced N7- and O6-alkylguanine adducts are not pref

106 nase gene was not expressed in three of five NNK-induced lung tumor-derived cell lines or in a sponta

107 h ERK1/2 and PKCalpha, which is required for NNK-induced survival and proliferation of human lung can

108 - and (S)-NNAL are formed metabolically from NNK in smokers.

109 airway epithelial cells and lung tumors from NNK-treated A/J mice, and in human lung cancers derived

110 Furthermore, NNK promotes secretion of active mu- and m-calpain from

111 12 occurred at a frequency of 35% and 40% in NNK- and VC-induced tumors, respectively, compared with

112 monary P450-mediated metabolic activation in NNK-induced lung cancer, and our mouse models should be

113 importance of pyridyloxobutyl DNA adducts in NNK-induced rat lung tumorigenesis, the first study in t

114 tant role for pyridyloxobutyl DNA adducts in NNK-induced rat lung tumorigenesis.

115 rms that PKCiota is a necessary component in NNK-mediated survival signaling.

116 lguanine adduct levels, without decreases in NNK bioavailability, consistent with decreased NNK bioac

117 nd 366 may also contribute to differences in NNK metabolism.

118 which are considered predisposing events in NNK-induced lung tumorigenesis.

119 T base changes, suggesting its importance in NNK mutagenesis and carcinogenesis.

120 level of active TGF-beta and thus increases NNK-induced lung tumorigenesis.

121 after NNK treatment significantly inhibited NNK-induced early bronchiolar cell proliferation on day

122 At relatively high doses, injected NNK is carcinogenic in rodents.

123 ine and nicotine-derived nitrosamine ketone (NNK).

124 Findings of the present study directly link NNK exposure to lung cancer development in humans.

125 Mechanistically, NNK-induced Bad phosphorylation prevents its interaction

126 mes are 93.5% identical, CYP2A13 metabolizes NNK with much lower K(m) values than does CYP2A6.

127 Moreover, NNK may also contribute to the development of smoking-re

128 Most NNK appeared rapidly in the blood draining the airway mu

129 and 0.6 ng/L, respectively, while NAB, NNN, NNK, and NNAL were not detected in the samples.

130 en HF (group 3) or LF (group 4) diets but no NNK, developed spontaneous lung tumors, the expression o

131 rculation, and 45 min after instillation, no NNK was found in the trachea or any distal tissue.

132 Neither butadiene nor NNK has been tested experimentally for a possible role i

133 LOH on chromosome 12 was observed in 45% of NNK-induced, 59% of VC-induced, 58% of aflatoxin B1 (AFB

134 ues, first-pass metabolism and activation of NNK in the airway mucosa were sufficiently rapid to caus

135 ate that the N7- and O(6)-guanine adducts of NNK are not overproduced at the endogenously methylated

136 ceptor demonstrated high affinity binding of NNK to each of these receptors.

137 ased metabolic activation and DNA binding of NNK.

138 butes predominantly to systemic clearance of NNK, thereby decreasing NNK-induced lung cancer.

139 important in estimating the contribution of NNK to lung cancer relative to other carcinogens and for

140 It has been shown that the development of NNK-induced ACs in mice is reduced by inhibitors of cycl

141 ugh the rapid absorption and distribution of NNK and its metabolites ensured widespread and extensive

142 A/J mice were treated with a single dose of NNK (103 mg/kg body weight, i.p.) and kept for 20 weeks

143 eeks old) were treated with a single dose of NNK (103 mg/kg of body weight, i.p.) on day 0, and the c

144 ea, starting 16 weeks after a single dose of NNK, inhibited the progression of adenoma to adenocarcin

145 of F344 rats treated with different doses of NNK (0.3, 1.0, 10.0, and 50 mg/kg; 3 x weekly for 2 week

146 ng tumor incidence at the different doses of NNK versus pyridyloxobutyl DNA adducts in Type II cells,

147 butanone (NNK) by measuring the frequency of NNK-induced chromosomal damage endpoints (micronuclei, n

148 port the hypothesis that PEITC inhibition of NNK-induced lung tumors is a result of decreased metabol

149 findings identify the direct interaction of NNK with beta-adrenergic, AA-dependent pathways as a nov

150 , but it varied with cell type and length of NNK treatment.

151 Metabolism of NNK to NNAL produces a chiral center.

152 The mixture of NNK plus BaP (2 micromol each) was administered by gavag

153 ung cancer (2.35 A) or with two molecules of NNK bound (2.1 A): one in the active site and one in a m

154 The numbers of NNK-induced lung tumors were reduced in the lung-Cpr-nul

155 cidence in the lung, a major target organ of NNK.

156 perhaps caffeine) inhibit the progression of NNK-induced lung adenoma to adenocarcinoma.

157 cells agreed well with the 50% reduction of NNK-induced lung tumors by PEITC.

158 that Bcl2 potently suppresses the repair of NNK-induced abasic sites of DNA lesions in association w

159 Bcl2 significantly accelerates the repair of NNK-induced DNA damage, indicating that c-Myc may be ess

160 furthering our understanding of the role of NNK as a cause of lung cancer in smokers.

161 In this study, we investigated the role of NNK-mediated Ca(2+) signalling in lung cancer formation.

162 On the basis of structural similarities of NNK with classic beta-adrenergic agonists, we tested the

163 nd mu-calpain and resulted in suppression of NNK-induced cell migration and invasion.

164 hosphorylation and results in suppression of NNK-induced proliferation.

165 analysis was used to determine the yields of NNK adducts at the isotopically labeled guanine and at u

166 Treatment with nicotine or NNK attenuated apoptosis caused by etoposide, ultraviole

167 Activation of Akt by nicotine or NNK occurred within minutes at concentrations achievable

168 Upon exposure to nicotine or NNK, cells express high levels of IKBKE protein and mRNA

169 GGTGGTGGT, etc., where [X]4 denotes a random NNK library).

170 I3C reduced NNK plus BaP-induced tumor multiplicity by 78% in experi

171 Similarly, NNK-induced risks were 2.3-, 45.5-, and 10-fold, respect

172 s of CYP2A13 with NNK reveal either a single NNK molecule in the active site with orientations corres

173 At the dose studied, NNK did not induce liver and pancreatic tumors in the tr

174 iated Ca(2+) influx significantly suppresses NNK-induced IGF2 exocytosis, transformation and tumorige

175 sor gene, suggesting that factors other than NNK adduct formation are responsible for mutagenesis at

176 These results confirm that NNK and NNAL are the disinfection byproducts (DBPs) resu

177 nation of individual alkaloids confirms that NNK and NNAL are produced from NIC, N-nitrosonornicotine

178 We discovered that NNK potently induces multisite Bad phosphorylation at Se

179 We demonstrate here that NNK exposure of CC10-knock-out (CC10-KO) mice causes a s

180 We report here that NNK simultaneously stimulates Bcl2 phosphorylation exclu

181 rgic agonists, we tested the hypothesis that NNK stimulates the growth of human AC cells via agonist-

182 We hypothesized that NNK or its metabolite, 4-(methylnitrosamino)-1-(3-pyridy

183 Our data indicate that NNK disrupts the regulated pathway of IGF2 exocytosis an

184 Our findings indicated that NNK potently induces phosphorylation of both mu- and m-c

185 vels of NNAL plus NNAL-Gluc, indicating that NNK is not formed endogenously from nicotine.

186 ota and Bad phosphorylation, indicating that NNK-induced Bad phosphorylation occurs at least in part

187 combined with Western blotting revealed that NNK induced phosphorylation of ERbeta, an effect that in

188 eduction of NIC to 1.1 ng/L, suggesting that NNK and NNAL were formed from NIC.

189 We report here for the first time that NNK induces increasingly higher levels of COX-2 expressi

190 The NNK metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-but

191 The NNK-treated group, given 2% black tea, showed a signific

192 gan 1 week before and ended 1 week after the NNK administration.

193 ering from 1 week before to 1 week after the NNK treatment, exhibited significant inhibition of lung

194 C were potent chemopreventive agents for the NNK-induced lung tumorigenesis in F344 rats, whereas NAC

195 l cavity tumor incidence was observed in the NNK-treated group.

196 The lung tumor incidences in the NNK-treated groups, fed a diet containing 4 mmol/kg (876

197 so rapid: within 18 min of instillation, the NNK parent compound had disappeared from the systemic ci

198 ine levels as well as renal clearance of the NNK metabolites correlated with number of tins or pouche

199 28 ppm) exerted no inhibitory effects on the NNK-induced lung tumorigenesis.

200 evaluated this hypothesis by quantifying the NNK metabolites, NNAL and its glucuronides (NNAL-Gluc),

201 ed to filtered air or were injected with the NNK solvent dimethylsulfoxide.

202 ts (3 micromol/g diet) before and throughout NNK treatment (1.76 mg/kg, three times weekly for 4, 8,

203 Thus, NNK could be a DBP and/or a contaminant in wastewater.

204 Thus, NNK-induced cell migration and invasion may occur, at le

205 Thus, NNK-induced functional cooperation of Bcl2 and c-Myc in

206 have increased expression after exposure to NNK also had increased expression in a number of lung ca

207 d by treatment with acetylated precursors to NNK diazohydroxides.

208 y reverse transcription-PCR and responded to NNK with the release of AA and an increase in DNA synthe

209 reporter assays showed that, in response to NNK, ERbeta stimulated transcription of serum responsive

210 ially inhibited DNA synthesis in response to NNK.

211 hose expression was increased in response to NNK.

212 hat the CBMN assay is extremely sensitive to NNK-induced genetic damage and may serve as a strong pre

213 and fully methylated CG dinucleotides toward NNK-derived methylating and pyridyloxobutylating species

214 One hundred ng of tritiated NNK were instilled in the distal trachea of the dog.

215 then removed and analyzed for the tritiated NNK and its metabolites.

216 the rapid absorption of most of the tritium, NNK was nonetheless extensively metabolized in the trach

217 oncurrence with LOH on chromosome 12 in VC-, NNK- and AFB1-induced tumors (P<0.05).

218 resence of a high-affinity compartment where NNK, NNAL, and/or NNAL-Gluc are retained or sequestered

219 Whereas NNK phosphorylated Akt at Thr(308) and Ser(473), ERbeta

220 cessation of smokeless tobacco use, in which NNK is administered p.o. rather than by inhalation.

221 users of snuff and chewing tobacco in which NNK is present in high concentrations.

222 in rats treated chronically or acutely with NNK in the drinking water support the conclusion that NN

223 an unbiased library of naive antibodies with NNK-randomized V(H) CDR3 loops converges upon mutants co

224 tumors in the peripheral lung in assays with NNK is significantly shorter in rats maintained on the H

225 52%, 60%, and 50% of tumors associated with NNK, vinyl carbamate, and methylene chloride, respective

226 pm; 16 weeks) or were injected biweekly with NNK (10 mg/kg, 16 weeks).

227 We also found that compared with NNK-treated WT mice, CC10-KO mice manifest increased fre

228 Additional structures of CYP2A13 with NNK reveal either a single NNK molecule in the active si

229 ecipitated with ERbeta, which increased with NNK treatment.

230 After incubation with NNK diazohydroxides, HPLC-ESI(+)-MS/MS analysis was used

231 and control wild-type mice were treated with NNK (100 mg/kg, i.p.) or saline vehicle.

232 ung and lung cells of F344 rats treated with NNK.