sarcophytol-a and epigallocatechin-gallate

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

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; Carcinogens; Catechin; Diterpenes; Humans; Mice; Sesquiterpenes; Skin Neoplasms

The tobacco-specific nitrosamines (TSNAs) are metabolites of nicotine and are major carcinogens in cigarette smoke. Chronic inflammation may promote the carcinogenic effect of these nitrosamines through the generation of oxygen radicals as evidenced by an increase in DNA strand breakage in cultured human lung cells treated with stimulated human phagocytes and TSNAs. Sarcophytol A (SaA), a simple monohydroxycembratetraene isolated from marine soft coral, and (-)-epigallocatechin galleate (EGCG), one of the main constituents of green tea, both inhibit tumor promotion. To evaluate their effect on TSNA-induced genetic damage, cultured human lung cells were pretreated with SaA or EGCG and then exposed to the TSNA 4-(N-methyl-N-n-trosamino)-1-(3-pyridyl)-1-butanone (NNK) and stimulated human phagocytes and then assayed for single-strand DNA breaks. Both SaA and EGCG provided significant protection against the induction of genetic damage in these cells and may prove useful in the chemoprevention of tobacco-induced carcinogenesis.

Topics: Anticarcinogenic Agents; Catechin; Cells, Cultured; Diterpenes; DNA; DNA Damage; Free Radicals; Humans; Hydrogen Peroxide; Lung; Nicotiana; Nitrosamines; Oxidative Stress; Phagocytes; Plants, Toxic; Reactive Oxygen Species; Superoxides; Tea; Tetradecanoylphorbol Acetate

Mechanisms of cancer prevention were studied using structurally different cancer-preventive agents, sarcophytol A, canventol, (-)-epigallo-catechin gallate, and tamoxifen, based on our evidence that tumor necrosis factor alpha (TNF-alpha) acts as an endogenous tumor promoter relevant to human carcinogenesis. Pretreatment with the four preventive agents commonly inhibited TNF-alpha mRNA expression and TNF-alpha release in BALB/3T3 cells induced by a tumor promoter, okadaic acid, whereas the expression of early response genes (c-jun, junB, c-fos, and fosB) was enhanced. These results strongly suggest that inhibition of TNF-alpha mRNA expression and its release is a new process of cancer prevention.

Topics: 3T3 Cells; Animals; Anticarcinogenic Agents; Base Sequence; Catechin; Cyclohexanols; Diterpenes; Humans; Mice; Molecular Sequence Data; Proto-Oncogenes; Tamoxifen; Tumor Necrosis Factor-alpha

12-O-Tetradecanoylphorbol-13-acetate (TPA)-mediated oxidative stress in HeLa cells and its inhibition were studied by fluorometric measurement of H2O2 and by 3H-postlabeling of the oxidized bases 8-hydroxyl-2'-deoxyguanosine (8-OHdG) and 5-hydroxymethyl-2'-deoxyuridine (HMdU). TPA treatment (10 fmol/cell) caused approximately 7-fold increase in H2O2 levels (0.1 nmol TPA/ml), and 5-10-fold increase in 8-OHdG and HMdU (10 nmol TPA/ml). Naturally occurring compounds [caffeic acid phenethyl ester (CAPE), (-).epigallocatechin gallate (EGCG), penta-O-galloyl-beta-D-glucose (PGG) and sarcophytol A (Sarp A)] and the anticancer drug tamoxifen (TAM) were tested as potential chemopreventive agents. These agents dose-dependently inhibited TPA-induced H2O2, 8-OHdG and HMdU. The doses required for a 50% decrease in H2O2 were approximately 2.5 microM for TAM; 5 microM for CAPE, EGCG and PGG; and 75 microM for Sarp A. TAM and PGG (10 microM), EGCG (25 microM), and CAPE (50 microM) abolished TPA-mediated H2O2 production, even below the normal cellular levels. TAM (2.5-20 microM) decreased TPA-mediated HMdU and 8-OHdG formation 2-29 times. Maximum inhibition occurred at 20 microM TAM, which caused an approximately 95% decline in HMdU and 8-OHdG. CAPE was effective at 0.5-50 microM. CAPE (25 microM) decreased 8-OHdG 95%, and HMdU 58%, while Sarp A (250 microM) reduced 8-OHdG by 93% and HMdU by 78%. EGCG (1-25 microM) and PGG (1-10 microM) inhibited of 8-OHdG and HMdU dose-dependently. However, higher doses (50 and 100 microM) decreased the efficacy of that inhibition. Of those agents tested, TAM appears to be the most and Sarp A the least effective. Our results point to these 5 compounds as being potential chemopreventive agents, which at very low doses decrease the tumor promoter-mediated oxidative processes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Anticarcinogenic Agents; Antineoplastic Agents; Caffeic Acids; Catechin; Deoxyguanosine; Diterpenes; DNA, Neoplasm; HeLa Cells; Humans; Hydrogen Peroxide; Hydrolyzable Tannins; Oxidation-Reduction; Phenylethyl Alcohol; Tamoxifen; Tannins; Tetradecanoylphorbol Acetate; Thymidine

Incubation of whole bovine lens with 10(-7) M 12-O-tetradecanoylphorbol-13-acetate (TPA) led to the lens opacity within 24 h. The hydrogen peroxide (H2O2) concentration in the whole lens was elevated 4 fold after treatment with either 10(-7) M TPA or 2.5 mM glucose/20 microM glucose oxidase. The lens opacification and H2O2 elevation were TPA dose-dependent. Preincubation of the lens with anti-tumor promoting agents EGCG (epigallocatechin gallate) or Sarp A (sarcophytol A) stopped the TPA-mediated opacification process and suppressed H2O2 elevation.

Topics: Animals; Antineoplastic Agents; Cataract; Catechin; Cattle; Diterpenes; Glucose; Glucose Oxidase; Hydrogen Peroxide; Lens, Crystalline; Tetradecanoylphorbol Acetate