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

Abstract

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)

4-Methylnitrosamino-1-3-pyridyl-1-butanone (NNK) promotes lung cancer cell survival by stimulating thromboxane A2 and its receptor

“…A linkage between the level of phosphorylated JNK and the sensitivity to TxA 2 has been previously reported in cells of other tumor types (Miggin and Kinsella, 2001;Li et al, 2007), whereas studies in lung cancer cells have found no correlation . The data on the response of p38 phosphorylation to NNK in cancer studies are limited, whereas it has been well established that NNK can stimulate JNK activation in lung cancer of animal models (Kim et al, 2006;Lu et al, 2006). In this study, the phosphorylated p38 was shown to be influenced only by TxA 2 , whereas activation of JNK was demonstrated to be stimulated merely by NNK.…”

Inhibition of carcinogenesis by tea constituents

“…In our recent study, the oral administration of 0.5% Polyphenon E (PPE, a standardized green tea polyphenol preparation containing 65% EGCG, 25% other catechins, and 0.6% caffeine) or 0.044% caffeine in the drinking fluid for 32 weeks was found to inhibit the progression of lung adenomas to adenocarcinomas in A/J mice that had been treated with a single dose of NNK 20 weeks earlier [17]. Immunohistochemical (IHC) analysis showed that PPE and caffeine treatment inhibited cell proliferation in adenocarcinomas, enhanced apoptosis in adenocarcinomas and adenomas, and decreased levels of c-Jun and phospho-Erk1/2.…”

“…Administration of green tea, black tea, EGCG, or theaflavins during initiation or promotion stages was shown to significantly decrease (4-methylnitrosamino)-1-(3-pyridyl)-1-butanon (NNK)-induced lung tumorigenesis in rats, mice, or hamsters [9][10][11][12][13][14][15][16][17]. Treatment with green or black tea for 60 weeks also inhibited the spontaneous formation of lung tumors in A/J mice [18].…”

Caffeine Inhibits Cell Proliferation and Regulates PKA/GSK3β Pathways in U87MG Human Glioma Cells

“…Caffeine has also been reported to induce p53-independent G 1 -phase arrest in lung adenocarcinoma cell lines (Qi et al, 2002). Additionally, caffeine has been shown to inhibit epidermal growth factor (EGF)-induced cell transformation in the JB6 mouse epidermal cell line (Nomura et al, 2005), inhibit the progression of lung adenoma to adenocarcinoma (Lu et al, 2006), and suppress metastasis in a transgenic mouse model of mammary tumors .…”