Chemopreventive activity of selenocysteine prodrugs against tobacco‐derived nitrosamine (NNK) induced lung tumors in the A/J mouse

Li, Liang; Xie, Yang; El‐Sayed, Wael M.; Szakacs, Juliana G.; Franklin, Michael R.; Roberts, Jeanette C.

doi:10.1002/jbt.20105

Cited by 43 publications

(41 citation statements)

References 64 publications

(77 reference statements)

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“…Such an extent of body weight reduction unlikely contributes to the observed reduction of tumor multiplicities because quite a few candidates, including sulfurophane (52), benzyl isothiocyanate-N-acetylcysteine and phenethyl isothiocyanate-N-acetylcysteine (45), N-acetylcysteine (71), and isotretinoin (72), all could induce 5% to 20% body weight loss in A/J mice at specific dosages, whereas such treatments do not affect the lung tumor multiplicity induced by NNK, B[a]P, or tobacco smoke. Reduction in body weight is also not uncommon for chemopreventive candidates: Phenethyl isothiocyanate (52), selenium compounds (73,74), indole-3-carbinol (47), budesonide (75), and dexamethasone (50) all induce >10% body weight loss. Kava treatment alone also did not affect liver weight or enzymatic levels of ALT, AST, and GGT (Table 2; group 1 versus group 3).…”

Section: Discussionmentioning

confidence: 99%

Chemopreventive Effect of Kava on 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone plus Benzo[a]pyrene–Induced Lung Tumorigenesis in A/J Mice

Johnson

Kassie

O’Sullivan

et al. 2008

Cancer Prevention Research

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Lung cancer is the leading cause of cancer death, and chemoprevention is a potential strategy to help control this disease. Epidemiologic survey indicates that kava may be chemopreventive for lung cancer, but there is a concern about its potential hepatotoxicity. In this study, we evaluated whether oral kava could prevent 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) plus benzo[a]pyrene (B[a]P)-induced lung tumorigenesis in A/J mice. We also studied the effect of kava to liver. At a dose of 10 mg/g diet, 30-week kava treatment (8 weeks concurrent with NNK and B[a]P treatment followed by 22 weeks post-carcinogen treatment) effectively reduced lung tumor multiplicity by 56%. Kava also reduced lung tumor multiplicity by 47% when administered concurrently with NNK and B[a]P for 8 weeks. Perhaps most importantly, kava reduced lung tumor multiplicity by 49% when administered after the final NNK and B[a]P treatment. These results show for the first time the chemopreventive potential of kava against lung tumorigenesis. Mechanistically, kava inhibited proliferation and enhanced apoptosis in lung tumors, as shown by a reduction in proliferating cell nuclear antigen (PCNA), an increase in caspase-3, and cleavage of poly(ADP-ribose) polymerase (PARP). Kava treatment also inhibited the activation of nuclear factor κBNF-κB, a potential upstream mechanism of kava chemoprevention. Although not rigorously evaluated in this study, our preliminary data were not suggestive of hepatotoxicity. Based on these results, further studies are warranted to explore the chemopreventive potential and safety of kava.

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Section: Discussionmentioning

confidence: 99%

Chemopreventive Effect of Kava on 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone plus Benzo[a]pyrene–Induced Lung Tumorigenesis in A/J Mice

Johnson

Kassie

O’Sullivan

et al. 2008

Cancer Prevention Research

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“…1 Subsequently, many epidemiological and experimental animal studies suggested that Se has a chemopreventive effect role on cancer. [2][3][4][5][6][7] However, the molecular mechanisms of its anti-cancer activity are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

The JNK signaling pathway is involved in sodium-selenite-induced apoptosis mediated by reactive oxygen in HepG2 cells

Zou

Niu²,

Yang³

et al. 2008

Cancer Biology & Therapy

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Selenium compounds as effective chemopreventive agents can induce apoptosis in tumor cells, and reactive oxygen species (ROS) are important mediators in apoptosis induced by various stimuli including chemopreventive agents. The major mitogen-activated protein kinases (MAPKs), c-JUN N-terminal kinase (JNK), p38 and extracelluar signal-regulated kinase (ERK) are three kinases that have been shown to regulate apoptosis. In this study, we showed that selenite-induced apoptosis in HepG2 cells was mediated by ROS that activated JNK to regulate apoptosis. The selenite-treated HepG2 cells showed a dose-and time-dependent decrease in cell viability that was coincident with increased the levels of the apoptosis rate. The levels of selenite-induced ROS as measured by 2', 7'-dichlorofluorescein diacetate (DCFH-DA) fluorescence also showed a dose-and time-dependent increase in HepG2 cells. The kinase activity of JNK was induced by selenite in a dose-dependent manner and HepG2 cells exposed to selenite (10 μM) for 4 h showed increased levels of phosphorylated JNK, which decreased when exposed for additional 4 h. In contrast, Sp600125, a specific inhibitor of JNK, remarkably blocked the apoptosis of HepG2 exposed to selenite. Furthermore, N-acetylcysteine (NAC), a known antioxidant, increased cell viability and decreased ROS generation. Moreover, NAC effectively blocked apoptosis and decreased the levels of phosphorylated JNK induced by selenite. These results revealed that JNK might be involved in seleniteinduced ROS-mediated apoptosis in HepG2 cells.

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“…The selenite inhibition of B[a]P mutagenicity was attributed to its inhibitory effect on arylhydrocarbon hydroxylase (CYP1A) activity [5,9] an action which decreases the bioactivating metabolism to mutagenic metabolites [4,10]. In animals, selenite was an effective chemopreventive agent against 7,12-dimethylbenz [a]anthracene-induced mammary tumors in mice [11][12][13] and rats [14] but was not effective against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced mouse lung adenomas [15,16] or azaserine-induced rat pancreatic and hepatic neoplasms [17]. Selenoamino acids and their derivatives have also been investigated for cancer chemopreventive properties but were not effective against all classes of mutagens tested [13,16,[18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

“…In animals, selenite was an effective chemopreventive agent against 7,12-dimethylbenz [a]anthracene-induced mammary tumors in mice [11][12][13] and rats [14] but was not effective against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced mouse lung adenomas [15,16] or azaserine-induced rat pancreatic and hepatic neoplasms [17]. Selenoamino acids and their derivatives have also been investigated for cancer chemopreventive properties but were not effective against all classes of mutagens tested [13,16,[18][19][20][21]. In the only published antimutagenesis study for these organic selenium compounds, neither selenomethionine nor Se-methylselenocysteine were effective against 2-amino-3-methylimidazole [4,5]quinoline [22].…”

Section: Introductionmentioning

confidence: 99%

The antimutagenicity of 2-substituted selenazolidine-4-(R)-carboxylic acids

El‐Sayed¹,

Hussin²,

Franklin³

2007

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Selenium can have cancer chemopreventive activity, although the mechanism of action has not been well defined. Selenazolidine-4-(R)-carboxylic acids (SCAs) were devised as prodrugs of Lselenocysteine, to provide selenium in a form and at a concentration commensurate with cancer chemopreventive activity. In the present study, a series of selenazolidines has been evaluated in the Salmonella typhimurium TA98 tester strain and all were found to possess antimutagenic activity. There was little difference between the seven selenazolidines in their effectiveness against either benzo[a]pyrene (B[a]P) or 3,6-bis(dimethylamino)acridine (acridine orange), agents which differ in their requirement for mammalian enzyme bioactivation for mutagenicity. Antimutagenic activity against acridine orange was dependent on selenazolidine concentration, and EC50 values were in the 5 -10 μM range. At 25 μM, the concentration tested in common for the two mutagens, the selenazolidines were more effective antimutagens against acridine orange than against B[a]P, with reductions in mutant frequency ranging from 54-71% for B[a]P and 79-93% for acridine orange. Efficacy against B[a]P was not enhanced when the concentration was increased to 50 μM. The similarity in efficacy among the selenazolidines against B[a]P mutagenicity, contrasted with intercompound differences in their ability to inhibit S9 CYP1A activity. The CYP1A Ki values ranged from a low of 63 μM (2-[2'-hydroxyphenyl]SCA) to a high of 1.1 mM (2-cyclohexylSCA), but all were above the concentration required to inhibit mutagenicity by 50%. Thus, all the SCAs possess antimutagenic activity against both B[a]P and acridine orange, the efficacy varies little between the individual selenazolidines, and for B[a]P, the efficacy is not proportional to the inhibitory effect on the mutagen bioactivating enzyme.

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Chemopreventive activity of selenocysteine prodrugs against tobacco‐derived nitrosamine (NNK) induced lung tumors in the A/J mouse

Cited by 43 publications

References 64 publications

Chemopreventive Effect of Kava on 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone plus Benzo[a]pyrene–Induced Lung Tumorigenesis in A/J Mice

Chemopreventive Effect of Kava on 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone plus Benzo[a]pyrene–Induced Lung Tumorigenesis in A/J Mice

The JNK signaling pathway is involved in sodium-selenite-induced apoptosis mediated by reactive oxygen in HepG2 cells

The antimutagenicity of 2-substituted selenazolidine-4-(R)-carboxylic acids

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