okadaic-acid and epigallocatechin-gallate

The classic two-stage chemical carcinogenesis in rodents is not directly linked to multistage carcinogenesis in humans. In light of our findings that tumor necrosis factor-α (TNF-α) is an endogenous tumor promoter and that TNF-α-inducing protein (Tipα) of Helicobacter pylori stimulates progression of cancer and epithelial-mesenchymal transition, we think it is necessary to re-examine the concept of tumor promoter, from chemicals to inflammatory proteins.. This paper begins with "inflammation," discovered by Virchow, studies of Yamagiwa and Tsutsui, and briefly reviews numerous topics, such as (1) the classic concept of tumor promoter, (2) tumor promotion on mouse skin induced by protein kinase C activators and okadaic acid class compounds, (3) organ specificity of tumor promoters, presenting numerous tumor promoters in various organs, (4) unique tumor promotion induced by inhibitors of protein phosphatases 1 and 2A in mouse skin, rat glandular stomach, and rat liver, (5) the significant role of TNF-α in tumor-promoting inflammation, (6) progression induced by Tipα of H. pylori, and (7) enhancement of cancer treatment efficacy with the combination of anticancer drugs and green tea catechins, to inhibit tumor-promoting inflammation.. Human cancer development involves both durable genetic changes caused by carcinogens and proinflammatory cytokines, and simultaneous inflammation in progression induced by proinflammatory cytokines and chemokines.

Topics: Animals; Anticarcinogenic Agents; Carcinogens; Catechin; Gastrointestinal Neoplasms; Helicobacter Infections; Humans; Inflammation; Inflammation Mediators; Neoplasms, Experimental; Okadaic Acid; Organ Specificity; Skin Neoplasms

The study of green tea polyphenols as a cancer preventative is approaching a new era, with significant results accumulating rapidly. This paper briefly reviews four topics related to mechanisms of action of tea polyphenols: (I) identification of the genes commonly affected by EGCG, as demonstrated by Clontech's Atlas cDNA Expression Array; (II) the significance of heterogeneous nuclear ribonucleoprotein B1 (hnRNP B1) as a new biomarker for early detection of lung cancer, and inhibition of its expression by EGCG; (III) the synergistic or additive effects of EGCG with the cancer preventive agents, sulindac and tamoxifen, on induction of apoptosis in PC-9 cells and on inhibition of intestinal tumor development in multiple intestinal neoplasia (Min) mice; (IV) the results of a 10 year prospective cohort study demonstrating the effectiveness of daily consumption of green tea in preventing cancer, and a prototype study for developing green tea beverage as cancer preventive.

Topics: Animals; Anticarcinogenic Agents; Biomarkers, Tumor; Carcinoma, Squamous Cell; Catechin; Chemoprevention; Cohort Studies; Drug Synergism; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Heterogeneous-Nuclear Ribonucleoprotein Group A-B; Heterogeneous-Nuclear Ribonucleoproteins; Humans; Intestinal Neoplasms; Japan; Lung Neoplasms; Male; Mice; Mice, Mutant Strains; Okadaic Acid; Oligonucleotide Array Sequence Analysis; Prospective Studies; Ribonucleoproteins; Sulindac; Tea; Tumor Cells, Cultured

In the normal human life span, there occur lifestyle-related diseases that may be preventable with nontoxic agents. This paper deals with the preventive activity of green tea in some lifestyle-related diseases. Green tea is one of the most practical cancer preventives, as we have shown in various in vitro and in vivo experiments, along with epidemiological studies. Among various biological effects of green tea, we have focused on its inhibitory effect on TNF-alpha gene expression mediated through inhibition of NF-kappaB and AP-1 activation. Based on our recent results with TNF-alpha-deficient mice, TNF-alpha is an endogenous tumor promoter. TNF-alpha is also known to be a central mediator in chronic inflammatory diseases such as rheumatoid arthritis and multiple sclerosis. We therefore hypothesized that green tea might be a preventive agent for chronic inflammatory diseases. To test this hypothesis, TNF-alpha transgenic mice, which overexpress TNF-alpha only in the lungs, were examined. The TNF-alpha transgenic mouse is an animal model of human idiopathic pulmonary fibrosis which also frequently develops lung cancer. Expressions of TNF-alpha and IL-6 were inhibited in the lungs of these mice after treatment with green tea in drinking water for 4 months. In addition, judging from the results of a prospective cohort study in Saitama Prefecture, Japan, green tea helps to prevent cardiovascular disease. In this study, a decreased relative risk of death from cardiovascular disease was found for people consuming over 10 cups of green tea a day, and green tea also had life-prolonging effects on cumulative survival. These data suggest that green tea has preventive effects on both chronic inflammatory diseases and lifestyle-related diseases (including cardiovascular disease and cancer), resulting in prolongation of life span.

Topics: Animals; Anticarcinogenic Agents; Carcinogens; Cardiovascular Diseases; Catechin; Cohort Studies; Cricetinae; Female; Gene Expression Regulation; Humans; Interleukin-6; Japan; Life Style; Lung; Male; Mice; Mice, Transgenic; Neoplasms, Experimental; NF-kappa B; Okadaic Acid; Phytotherapy; Primary Prevention; Prospective Studies; Pulmonary Fibrosis; Rats; Risk; Tea; Transcription Factor AP-1; Tumor Necrosis Factor-alpha

Tumor promotion is a critical point in multistage carcinogenesis in humans. We have identified a common biochemical and molecular tumor promotion mechanism, the okadaic acid pathway, applicable in various organs. Tumor promotion by the okadaic acid class of compounds is mediated through inhibition of protein phosphatases 1 and 2A, resulting in an increase of protein phosphorylation and a subsequent expression of cell proliferation genes. Recently, we demonstrated that okadaic acid induced the release of mouse tumor necrosis factor-alpha (mTNF-alpha) from BALB/3T3 cells. The first part of this review discusses the link between the okadaic acid pathway and TNF-alpha as endogenous tumor promoters in vivo. Inhibitors of tumor promotion are varied. For the purpose of cancer chemoprevention in humans, the inhibitors sarcophytol A, canventol, and (-)-epigallocatechin gallate (EGCG) were studied and the results are presented. The inhibitory mechanisms also were varied: sarcophytol A inhibited H2O2 formation by TPA-activated human polymorphonuclear leukocytes; canventol inhibited protein isoprenylation in the cells; and EGCG, which is a main constituent of Japanese green tea, is an antioxidant. These inhibitors are promising cancer chemopreventive agents. Study of the essential tumor promotion mechanisms will facilitate the development of cancer chemopreventive agents.

Topics: Anticarcinogenic Agents; Catechin; Cyclohexanols; Diterpenes; Ethers, Cyclic; Humans; Neoplasms; Okadaic Acid; Tumor Necrosis Factor-alpha

Among various biochemical and biological activities of tea polyphenols, we believe inhibition of the expression and release of tumor necrosis factor-alpha (TNF-alpha) is crucial, since our study with TNF-alpha-deficient mice has revealed that TNF-alpha is an essential factor in tumor promotion. We found that EGCG dose-dependently inhibited AP-1 and NF-kappaB activation in BALB/3T3 cells treated with okadaic acid, resulting in inhibition of TNF-alpha gene expression. Furthermore, treatment with 0.1% green tea extract in drinking water reduced TNF-alpha gene expression as well as TNF-alpha protein level in the lung of TNF-alpha transgenic mice; and IL-1beta and IL-10 gene expression in the lung was also inhibited by treatment with green tea extract, indicating that green tea inhibits both TNF-alpha and the cytokines induced by TNF-alpha in organs. We recently found synergistic effects of EGCG and cancer preventive agents such as tamoxifen and sulindac, on cancer preventive activity. Taken together, the results show that green tea is efficacious as a non-toxic cancer preventive for humans.

Topics: 3T3 Cells; Animals; Anticarcinogenic Agents; Catechin; Flavonoids; Gene Expression Regulation; Humans; Interleukin-1; Interleukin-10; Lung; Mice; Mice, Transgenic; Okadaic Acid; Phenols; Plant Extracts; Polymers; Recombinant Fusion Proteins; Tea; Tumor Necrosis Factor-alpha

It is now well accepted that (-)-epigallocatechin gallate (EGCG) inhibits carcinogenesis in the digestive tract in rodents. To understand the mechanisms of anticarcinogenesis, we first studied growth inhibition by EGCG in human stomach cancer cell lines established at Seoul National University (SNU cell lines). Inhibition by EGCG of [3H]thymidine incorporation into eight SNU cell lines was examined, in relation to transforming growth factor-beta (TGF-beta) responsiveness. Various tea polyphenols derived from green tea and black tea induced growth inhibition and apoptosis of human stomach cancer cell line KATO III, and inhibition of tumor necrosis factor-alpha (TNF-alpha) release from the cells, in the order of (-)-epicatechin gallate (ECG), EGCG, (-)-epigallocatechin (EGC), teaflavins (TF) and (-)-epicatechin (EC). In addition, we demonstrated that EGCG inhibited TNF-alpha gene expression in KATO III cells, as well as okadaic acid-induced AP-1 and NF-kappa B activation. The inhibitory potencies of EGCG for AP-1 and NF-kappa B binding to DNA were different between KATO III cells and mouse fibroblast cell line BALB/3T3. Thus, EGCG and other tea polyphenols may interact with various transcription factors, in addition to AP-1 and NF-kappa B, in nuclei of various cells, resulting in inhibition of TNF-alpha gene expression and TNF-alpha release.

Topics: 3T3 Cells; Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Catechin; Cell Division; Flavonoids; Gene Expression; Humans; Mice; Mice, Inbred BALB C; NF-kappa B; Okadaic Acid; Phenols; Phytotherapy; Polymers; Stomach Neoplasms; Tea; Transcription Factor AP-1; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

(-)-Epigallocatechin gallate (EGCG) was reported to inhibit protein kinase C (PKC) activation by 12-O-tetradecanoylphorbol-13-acetate (TPA), and inhibit interaction of tumor promoter with its receptors, named 'a sealing effect'. In order to clarify the sealing effect of EGCG, we prepared liposomes and examined inhibition of PKC activation by various concentrations of EGCG dispersed in the liposome. EGCG added to a liposome dispersion existed either in a buffer solution as aggregates or in phospholipid bilayer membranes, and EGCG disturbed membrane structure. The potency of inhibitory effect of EGCG on PKC activation was dependent on the nature of liposomes, indicating that interaction of EGCG with phospholipid bilayer membrane affects PKC activation. Moreover, EGCG prevented the binding of adenosine 5'-triphosphate and TPA to PKC, resulting in inhibition of PKC activation. On the other hand, the activity of protein phosphatase 2A (PP2A) was suppressed in the presence of liposomes, but was not influenced by EGCG. Moreover, EGCG recovered phosphatase activity of PP2A in a buffer solution, the activity of which was inhibited by okadaic acid. All the results indicated that EGCG possesses sealing effects in terms of PKC and PP2A, by inhibiting interaction of various ligands with proteins.

Topics: Catechin; Circular Dichroism; Enzyme Inhibitors; Lipid Bilayers; Liposomes; Okadaic Acid; Phosphoprotein Phosphatases; Protein Kinase C; Protein Phosphatase 2; Spectrometry, Fluorescence; Tetradecanoylphorbol Acetate

(-)-Epigallocatechin gallate (EGCG), the main constituent of green tea, inhibited a tumor promoting activity of okadaic acid in a two-stage carcinogenesis experiment on mouse skin. The group treated with a single application of 100 micrograms 7, 12-dimethylbenz (a) anthracene followed by repeated applications of 1 microgram okadaic acid resulted in 80% of tumor-bearing mice and 4.7 of average numbers of tumors per mouse in week 20. Repeated applications of 5 mg EGCG, prior to okadaic acid, completely inhibited the tumor formation in mice up to week 20. The inhibitory effects of EGCG with two different doses of each application, 1 mg and 5 mg, were dose-dependent. A topical application of 5 mg EGCG immediately reduced the specific binding of [3H]okadaic acid to a particulate fraction of mouse skin to as low as 30% of control. According to the Scatchard analysis, the reduction of specific [3H]okadaic acid binding was mainly due to the reduction of the binding sites, not due to the change of the affinity. The reduction of the specific binding was closely related to the inhibitory effct of EGCG on tumor promotion of okadaic acid. Since EGCG is a non-toxic compound, ingested in green tea in daily life in Japan, EGCG is one of the candidates for practical cancer chemopreventive agents.

Topics: Animals; Antineoplastic Agents; Binding Sites; Carcinogens; Catechin; Mice; Okadaic Acid; Skin Neoplasms; Tea