Efficacy of Polyphenon E, Red Ginseng, and Rapamycin on Benzo(a)pyrene-Induced Lung Tumorigenesis in A/J Mice

Yan, Yan; Wang, Yian; Tan, Qing; Hara, Yukihiko; Yun, Taik Koo; Lubet, Ronald A.; You, Ming

doi:10.1593/neo.05652

Cited by 59 publications

(49 citation statements)

References 41 publications

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“…In addition to preventing tumorigenesis, our data show that administration of rapamycin to established NNK-induced tumors decreases tumor size but does not affect tumor multiplicity. This is consistent with a study by Yan et al who showed that treatment with a higher dose of rapamycin (2.0 mg/kg) on a daily (5 of 7 days) schedule for 14 weeks, beginning 12 weeks after administration of a polycyclic aromatic hydrocarbon [benzo(a)pyrene], reduced lung tumor load by 84% (21). Similar to our results, Yan et al did not observe a reduction in tumor multiplicity.…”

Section: Discussionsupporting

confidence: 93%

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Identification of a Highly Effective Rapamycin Schedule that Markedly Reduces the Size, Multiplicity, and Phenotypic Progression of Tobacco Carcinogen–Induced Murine Lung Tumors

Granville

Warfel²,

Tsurutani³

et al. 2007

Clinical Cancer Research

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Purpose: Human and murine preneoplastic lung lesions induced by tobacco exposure are characterized by increased activation of theAkt/mammalian target of rapamycin (mTOR) pathway, suggesting a role for this pathway in lung cancer development. To test this, we did studies with rapamycin, an inhibitor of mTOR, in A/J mice that had been exposed to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Experimental Design: Tumorigenesis was induced by i.p. injection of NNK, and rapamycin was administered1or 26 weeks after NNK administration. Biomarkers associated with mTOR inhibition were assessed in lung and/or surrogate tissues using immunohistochemistry and immunoblotting. Rapamycin levels were measured using mass spectroscopy. Results: Rapamycin was administered on a daily (5 of 7 days) regimen beginning 26 weeks after NNK decreased tumor size, proliferative rate, and mTOR activity. Multiplicity was not affected. Comparing this regimen with an every-other-day (qod) regimen revealed that rapamycin levels were better maintained with qod administration, reaching a nadir of 16.4 ng/mL, a level relevant in humans. When begun 1 week after NNK, this regimen was well tolerated and decreased tumor multiplicity by 90%. Tumors that did develop showed decreased phenotypic progression and a 74% decrease in size that correlated with decreased proliferation and inhibition of mTOR. Conclusions:Tobacco carcinogen^induced lung tumors in A/J mice are dependent upon mTOR activity because rapamycin markedly reduced the development and growth of tumors. Combined with the Food and Drug Administration approval of rapamycin and broad clinical experience, these studies provide a rationale to assess rapamycin in trials with smokers at high risk to develop lung cancer.

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Section: Discussionsupporting

confidence: 93%

“…Combined with the results obtained by Wislez et al (20) and Yan et al (21), our data provide a strong rationale to consider testing rapamycin in smokers who are at high risk to develop lung cancer. What are the issues that limit the application of these findings to a clinical trial?…”

Section: Discussionsupporting

confidence: 78%

Identification of a Highly Effective Rapamycin Schedule that Markedly Reduces the Size, Multiplicity, and Phenotypic Progression of Tobacco Carcinogen–Induced Murine Lung Tumors

Granville

Warfel²,

Tsurutani³

et al. 2007

Clinical Cancer Research

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“…This preparation has been investigated extensively in terms of toxicology and pharmacokinetics, and is in phase I and phase II clinical chemoprevention trials at different institutions (25)(26)(27)(28). In the present study, the effects of Polyphenon E and caffeine on the progression of NNKinduced lung adenoma to adenocarcinoma in A/J mice were examined.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Adenoma Progression to Adenocarcinoma in a 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone–Induced Lung Tumorigenesis Model in A/J Mice by Tea Polyphenols and Caffeine

et al. 2006

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The present study investigated the inhibitory effects of Polyphenon E [a standardized green tea polyphenol preparation containing 65% (À)-epigallocatechin-3-gallate] and caffeine on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumor progression from adenoma to adenocarcinoma. Female A/J mice were treated with a single dose of NNK (103 mg/kg body weight, i.p.) and kept for 20 weeks for the mice to develop lung adenomas. The mice were then given a solution of 0.5% Polyphenon E or 0.044% caffeine as the sole source of drinking fluid until week 52. Both treatments significantly decreased the number of visible lung tumors. Histopathologic analysis indicated that Polyphenon E administration significantly reduced the incidence (by 52%) and multiplicity (by 63%) of lung adenocarcinoma. Caffeine also showed marginal inhibitory effects in incidence and multiplicity of adenocarcinoma (by 48% and 49%, respectively). Markers of cell proliferation, apoptosis, and related cell signaling were studied by immunohistochemistry, and the labeling index and staining intensity were quantified by the Image-Pro system. Polyphenon E and caffeine treatment inhibited cell proliferation (by 57% and 50%, respectively) in adenocarcinomas, enhanced apoptosis in adenocarcinomas (by 2.6-and 4-fold, respectively) and adenomas (both by 2.5-fold), and lowered levels of c-Jun and extracellular signal-regulated kinase (Erk) 1/2 phosphorylation. In the normal lung tissues, neither agent had a significant effect on cell proliferation or apoptosis. The results show that tea polyphenols (and perhaps caffeine) inhibit the progression of NNK-induced lung adenoma to adenocarcinoma. This effect is closely associated with decreased cell proliferation, enhanced apoptosis, and lowered levels of c-Jun and Erk1/2 phosphorylation. (Cancer Res 2006; 66(23): 11494-501)

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“…We have shown that 0.5% PPE in drinking fluid, given during weeks 20 to 52 after NNK treatment, significantly inhibits lung tumor progression from adenoma to adenocarcinoma (8). It has also been shown that PPE given at the postinitiation stage significantly lowers both tumor multiplicity and tumor load in a dose-dependent manner in a benzo(a)pyrene-induced lung tumor model (9). The National Cancer Institute has assisted the development of PPE as an agent for human chemoprevention studies.…”

mentioning

confidence: 85%

Synergistic Inhibition of Lung Tumorigenesis by a Combination of Green Tea Polyphenols and Atorvastatin

Lǚ

Xiao

You

et al. 2008

Clinical Cancer Research

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Purpose: The present study investigated the possible synergistic inhibitory effect of a novel combination of polyphenon E (PPE, a standardized green tea polyphenol preparation) and atorvastatin (trade name Lipitor) in a mouse tumorigenesis model and in human lung cancer H1299 and H460 cell lines. Experimental Design: Female A/J mice were given two weekly i.p. injections of 4-(methylnitrosaminao)-1-(3-pyridyl)-1-butanone (150 mg/kg total dose); 1 week later, mice were treated with PPE (0.25% or 0.5 % in drinking fluid), atorvastatin (200 or 400 ppm in diet), or PPE (0.25%) plus atorvastatin (200 ppm) for 16 weeks. The interaction of these two agents was also studied in human lung cancer H1299 and H460 cells. Results: The individual agents, PPE or atorvastatin, were not effective in inhibiting lung tumorigenesis. The low-dose combination of PPE and atorvastatin, however, significantly reduced both the tumor multiplicity and tumor burden (by 56% and 55%, respectively, P < 0.05). Isobologram analysis of the interaction of the two agents indicated that the combination synergistically decreased tumor multiplicity (P = 0.0006) and tumor burden (P = 0.0009). The inhibition was associated with enhanced apoptosis and suppressed myeloid cell leukemia 1 (Mcl-1) level in adenoma as determined by immunohistochemistry and Western blots. Treatment with combinations of PPE and atorvastatin also synergistically decreased the number of viable H1299 and H460 cells as determined by isobologram analysis. This synergistic effect was associated with increased apoptosis as determined by the terminal deoxyribonucleotide transferase^mediated nick-end labeling assay. The combination of PPE and atorvastatin was more efficient in reducing the antiapoptotic protein Mcl-1 level and increasing the cleaved caspase-3 and cleaved poly(ADP)-ribose polymerase level than the single-agent treatment.Conclusions: The present work showed that PPE and atorvastatin synergistically inhibited 4-(methylnitrosaminao)-1-(3-pyridyl)-1-butanone^induced lung tumorigenesis in mice and the growth of lung cancer H1299 and H460 cells, possibly through enhanced apoptosis. The results provide leads for future research on the application of this combination for the prevention and treatment of lung cancer.

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Efficacy of Polyphenon E, Red Ginseng, and Rapamycin on Benzo(a)pyrene-Induced Lung Tumorigenesis in A/J Mice

Cited by 59 publications

References 41 publications

Identification of a Highly Effective Rapamycin Schedule that Markedly Reduces the Size, Multiplicity, and Phenotypic Progression of Tobacco Carcinogen–Induced Murine Lung Tumors

Identification of a Highly Effective Rapamycin Schedule that Markedly Reduces the Size, Multiplicity, and Phenotypic Progression of Tobacco Carcinogen–Induced Murine Lung Tumors

Inhibition of Adenoma Progression to Adenocarcinoma in a 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone–Induced Lung Tumorigenesis Model in A/J Mice by Tea Polyphenols and Caffeine

Synergistic Inhibition of Lung Tumorigenesis by a Combination of Green Tea Polyphenols and Atorvastatin

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