Antioxidant activities of thermally treated Sesamum indicum L. leaf extracts and their inhibitory effects against growth and metastatic properties of human colon cancer cells.

The study aimed to investigate antioxidant activities of two different thermally treated sesame (Sesamum indicum L.) leaf ethanol extract, steamed sesame leaf extract (SSLE) and roasted sesame leaf extract (RSLE), and their inhibitory effects on uncontrolled growth and increased metastatic properties in human colon cancer cell lines. Both SSLE and RSLE contained pedaliin as the major polyphenol and its aglycon, pedalitin, as a minor component and exhibited radical scavenging activities and ferric reducing antioxidant power. SSLE and RSLE decreased growth of HT29 and HCT116 colon cancer cells, which was attributed to the induction of apoptosis and cell cycle arrest at either G2/M (by SSLE in HCT116) or S phase (by RSLE in HCT116). Furthermore, SSLE and RSLE inhibited migration and adhesion in both cell lines. These results indicate that thermally treated sesame leaves retained pedaliin content and exhibited antioxidant activities and inhibitory activities against the growth and metastatic properties of colon cancer cells.

In Vitro Antioxidant and Anti-Colon Cancer Activities of Sesamum indicum L. Leaf Extract and Its Major Component, Pedaliin.

Sesame (Sesamum indicum L.) leaves (SLs) are used as vegetables and traditional medicines in Asian and African countries. We investigated in vitro antioxidant and anti-colon cancer efficacy of ethanol extract of SL (SLE) and its major bioactive component. SLE contained appreciable amount of major classes of antioxidant phytochemicals, such as total polyphenols, total flavonoids, and carotenoids, and correspondingly exhibited antioxidant activities, such as radical scavenging activity and ferric reducing antioxidant power (FRAP). A cell viability assay showed that SLE time- and dose-dependently attenuated the growth of human colon cancer cells, HT29 and HCT116. Flow cytometry analysis showed that SLE increased sub-G1 (in HT29 and HCT116) and G2/M (in HCT116) cell populations, suggesting that the growth inhibition by SLE was due to induction of apoptosis and G2/M cell cycle arrest. Trans-well and wound-healing assays showed that SLE alleviated invasion and migration of HT29 and HCT116 cells in non-cytotoxic conditions. High-performance liquid chromatography analysis revealed that pedaliin (6-hydroxylueolin 7-methyl ether 6-glucoside; pedalitin-6-O-glucoside) was a major constituent of SLE. Moreover, FRAP, growth-inhibitory, anti-invasive, and anti-migratory activities of pedaliin were found. These results demonstrated that SLE possesses in vitro antioxidant and anti-colon cancer activities and that pedaliin is a major component contributing to such activities.

Antirrhinum majus L. flower extract inhibits cell growth and metastatic properties in human colon and lung cancer cell lines.

Snapdragon ( Antirrhinum majus L.) flowers are one of the most frequently used edible flowers in different preparations of foods and drinks. In this study, we examined inhibitory effects of snapdragon flower extract (SFE) against distinctive properties of cancer cells, stimulated growth, and activated metastasis, using H1299 lung cancer and HCT116 colon cancer cell lines. SFE treatment at 100-1,000 µg/ml for 24-72 hr resulted in a time- and dose-dependent growth inhibition in H1299 and HCT116 cells. Cell cycle analysis and Annexin V staining assay further revealed that SFE caused cell cycle arrest at G2/M phase and induction of apoptosis, indicating the growth inhibition by SFE is attributed to its G2/M cell cycle-arresting and apoptosis-inducing activities. SFE dose-dependently enhanced generation of intracellular reactive oxygen species (ROS) and reduced mitochondrial membrane potential in H1299 cells but had no effect on intracellular ROS levels in HCT116 cells, suggesting that the type of apoptosis induced by SFE in H1299 cells is different to that in HCT116 cells. Furthermore, SFE alleviated invasion, levels of matrix metalloproteinases, migration, and adhesion in H1299 and HCT116 cells. These results indicate that SFE not only inhibits cell growth by cell cycle arrest at G2/M and apoptosis induction but also alleviates metastatic properties such as invasion, migration, and adhesion in lung and colon cancer cells.

Perilla frutescens Britton var. frutescens leaves attenuate dextran sulfate sodium-induced acute colitis in mice and lipopolysaccharide-stimulated angiogenic processes in human umbilical vein endothelial cells.

The aim of the current study was to investigate whether the leaves of Perilla frutescens Britton var. frutescens (PL), a frequently consumed vegetable in Korea, attenuate dextran sulfate sodium (DSS)-induced acute colitis in mice and lipopolysaccharide (LPS)-stimulated angiogenic processes in human umbilical vein endothelial cells (HUVEC). In DSS-treated mice, dietary supplementation with PL mitigated DAI and colon shortening. The dietary PL also reduced colonic levels of inflammatory and angiogenic mediators, such as interleukin-1ß, interleukin-6, monocyte chemoattractant protein-1, macrophage inflammatory protein-2, leukotriene B4, inducible nitric oxide synthase, cyclooxygenase-2, basic fibroblast growth factor, and intercellular adhesion molecule-1 (ICAM-1). Treatment of HUVEC with ethanol extract of PL attenuated LPS-stimulated increases in ICAM-1 levels, monocyte adhesion, invasion, and tube formation. This study suggests that dietary PL effectively inhibited DSS-induced acute colitis in mice, and its anti-angiogenic activities may partially contribute to the inhibition.

Green Tea Polyphenols Inhibit Colorectal Tumorigenesis in Azoxymethane-Treated F344 Rats.

In studying the cancer-preventive activities of green tea polyphenols, we previously demonstrated that dietary administration of polyphenon E (PPE) inhibited the formation of aberrant crypt foci (ACF) in the colon of azoxymethane (AOM)-treated F344 rats. Herein, we reported cancer-preventive activity of PPE using colorectal cancer as an end point. F344 rats were given two weekly injections of AOM, and then maintained on a 20% high-fat diet with or without 0.24% PPE for 34 wk. In the control group, 83% of rats developed colorectal tumors. Dietary PPE treatment significantly increased the plasma and colonic levels of tea polyphenols, and decreased tumor multiplicity and tumor size. Histological analysis indicated that PPE significantly decreased the incidence of adenocarcinoma, and the multiplicity of adenocarcinoma as well as the multiplicity of adenoma. PPE treatment significantly decreased plasma levels of proinflammatory eicosanoids, prostaglandin E2, and leukotriene B4. It also decreased ß-catenin nuclear expression, induced apoptosis, and increased expression levels of RXRα, ß, and γ in adenocarcinomas. In conclusion, our results convincingly demonstrated the inhibitory effects of orally administered PPE on colon carcinogenesis in AOM-treated rats and suggested possible biomarkers for the biological effects of green tea polyphenols.

Glycine max Merr. leaf extract possesses anti-oxidant properties, decreases inflammatory mediator production in murine macrophages, and inhibits growth, migration, and adhesion in human cancer cells.

The present study aimed to investigate the in vitro anti-oxidant, anti-inflammatory, and anticancer properties of the ethanol extract of soybean (Glycine max Merr.) leaves (SLE). The total polyphenol and flavonoid levels were 142.0±14.0mg gallic acid equivalent/g and 104.9±2.0 mg quercetin equivalent/g, respectively. The radical scavenging activity and ferric-reducing anti-oxidant power of SLE at the concentrations of 125-500 µg/mL were 5-61%. In lipopolysaccharide-treated RAW 264.7 macrophages, treatment with SLE at concentrations of 62.5-500 µg/mL dose-dependently decreased the production of nitric oxide and prostaglandin E2. In both HCT116 human colon cancer cells and H1299 human lung cancer cells, treatment with SLE inhibited the growth and anchorage-independent colony formation. SLE was also effective in inhibiting the migration of H1299 cells and the adhesion of both HCT116 and H1299 cells. These results suggest that SLE exerts anti-oxidant, antiinflammatory, and anti-cancer activities in vitro. It needs to be determined whether similar effects are reproduced in vivo.

Anti-cancer activities of Brassica juncea leaves in vitro.

Mustard (Brassica juncea) leaves are commonly consumed in different Asian and African countries. Cancer is a major burden of disease worldwide, and the colorectal and lung cancers are the leading cause of morbidity and mortality among cancers. In the current study, we aimed to investigate the effects of ethanol extract of mustard leaf (MLE) on the growth, angiogenic, and metastatic potentials of HCT116 colorectal carcinoma and H1299 non-small cell lung carcinoma cells in vitro. Treatment of HCT116 and H1299 cells with MLE inhibited cell growth in a dose-dependent manner (in the range of 175-700 µg/ml, by 39-86 %) and anchorage-independent colonization (at 700 µg/ml, by 56-86 %). Induction of apoptosis by MLE was evidenced by heterogeneous and condensed nucleus morphology, increased 4',6-diamidino-2-phenylindole dihydrochloride staining intensity, and elevated sub-G1 cell population. In both HCT116 and H1299 cells, treatment with MLE markedly suppressed the secretion of key pro-angiogenic factors, such as vascular endothelial cell growth factor (by >92 %) and basic fibroblast growth factor (by 73-94 %). MLE was also effective in inhibiting critical events during metastasis, such as invasion (by 18-33 % in HCT116 and H1299), migration (45-82 % in H1299), and adhesion (by 17-45 % in HCT116 and H1299). These results indicate that MLE possesses in vitro anti-cancer activities against colon and lung cancers. It needs to be verified whether similar effects are reproduced in vivo.

Inhibitory activities of Perilla frutescens britton leaf extract against the growth, migration, and adhesion of human cancer cells.

BACKGROUND/OBJECTIVES: Perilla frutescens Britton leaves are a commonly consumed vegetable in different Asian countries including Korea. Cancer is a major cause of human death worldwide. The aim of the current study was to investigate the inhibitory effects of ethanol extract of perilla leaf (PLE) against important characteristics of cancer cells, including unrestricted growth, resisted apoptosis, and activated metastasis, using human cancer cells. MATERIALS/METHODS: Two human cancer cell lines were used in this study, HCT116 colorectal carcinoma cells and H1299 non-small cell lung carcinoma cells. Assays using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide were performed for measurement of cell growth. Soft agar and wound healing assays were performed to determine colony formation and cell migration, respectively. Nuclear staining and cell cycle analysis were performed for assessment of apoptosis. Fibronectin-coated plates were used to determine cell adhesion. RESULTS: Treatment of HCT116 and H1299 cells with PLE resulted in dose-dependent inhibition of growth by 52-92% (at the concentrations of 87.5, 175, and 350 µg/ml) and completely abolished the colony formation in soft agar (at the concentration of 350 µg/ml). Treatment with PLE at the 350 µg/ml concentration resulted in change of the nucleus morphology and significantly increased sub-G1 cell population in both cells, indicating its apoptosis-inducing activity. PLE at the concentration range of 87.5 to 350 µg/ml was also effective in inhibiting the migration of H1299 cells (by 52-58%) and adhesion of both HCT116 and H1299 cells (by 25-46%). CONCLUSIONS: These results indicate that PLE exerts anti-cancer activities against colon and lung cancers in vitro. Further studies are needed in order to determine whether similar effects are reproduced in vivo.

Cancer prevention by tocopherols and tea polyphenols.

Tocopherols (vitamin E) and tea polyphenols have been reported to have cancer preventive activities. Large-scale human trials with high doses of alpha-tocopherol, however, have produced disappointing results. This review presents data showing that - and -tocopherols inhibit colon, lung, mammary and prostate carcinogenesis in animal models, whereas -tocopherol is ineffective in animal and human studies. Possible mechanisms of action are discussed. A broad cancer preventive activity of green tea polyphenols has been demonstrated in animal models, and many mechanisms have been proposed. The cancer preventive activity of green tea in humans, however, has not been conclusively demonstrated and remains to be further investigated.

Inhibitory effects of calcium against intestinal cancer in human colon cancer cells and Apc(Min/+) mice.

The aim of the study was to investigate the inhibitory effects of calcium against intestinal cancer in vitro and in vivo. We first investigated the effects of calcium treatment in HCT116 and HT29 human colon cancer cells. At the concentration range of 0.8-2.4 mM, calcium significantly inhibited cell growth (by 9-29%), attachment (by 12-26%), invasion (by 15-31%), and migration (by 19-61%). An immunofluorescence microscope analysis showed that the treatment with calcium (1.6 mM) for 24 h increased plasma membrane ß-catenin but decreased nuclear ß-catenin levels in HT29 cells. We then investigated the effect of dietary calcium on intestinal tumorigenesis in Apc(Min/+) mice. Mice received dietary treatment starting at 6 weeks of age for the consecutive 8 weeks. The basal control diet contained high-fat (20% mixed lipids by weight) and low-calcium (1.4 mg/g diet) to mimic the average Western diet, while the treatment diet contained an enriched level of calcium (5.2 mg calcium/g diet). The dietary calcium treatment decreased the total number of small intestinal tumors (by 31.4%; P < 0.05). The largest decrease was in tumors which were ≥ 2 mm in diameter, showing a 75.6% inhibition in the small intestinal tumor multiplicity (P < 0.001). Immunohistochemical analysis showed significantly reduced nuclear staining of ß-catenin (expressed as nuclear positivity), but increased plasma membrane staining of ß-catenin, in the adenomas from the calcium-treated groups in comparison to those from the control group (P < 0.001). These results demonstrate intestinal cancer inhibitory effects of calcium both in human colon cancer cells and Apc(Min/+) mice. The decreased ß-catenin nuclear localization caused by the calcium treatment may contribute to the inhibitory action.

Deleterious effects of high concentrations of (-)-epigallocatechin-3-gallate and atorvastatin in mice with colon inflammation.

Epigallocatechin-3-gallate (EGCG), atorvastatin (ATST), and their combination have been previously shown to inhibit colon carcinogenesis in animal models. We further investigated their inhibitory activities in azoxymethane (AOM) and dextran sulfate sodium (DSS)-treated Balb/cJ mice and CD-1 mice in 2 slightly different models. The mice were maintained on the AIN93M diet, or a similar diet containing 0.03%, 0.1%, or 0.3% EGCG; 60-ppm ATST; or a combination of 0.1% EGCG and 60-ppm ATST. Unexpectedly, no significant inhibitory activity was observed, and some of the treatment groups resulted in higher tumor multiplicity. To study the effects of EGCG on colon inflammation, CD-1 or C57BL/6 mice were treated with 1.5% DSS for 7 days and sacrificed 3 days later. DSS induced rectal bleeding and colon shortening; treatment with 0.5% EGCG exacerbated the bleeding and decreased mouse body weight. Dietary 0.5% EGCG also increased serum levels of leukotriene B4 and prostaglandin E2. These results suggest that, in mice bearing colon inflammation, high concentrations of EGCG and ATST enhance colon bleeding and may promote colon carcinogenesis.

Inhibition of IGF-1 signaling by genistein: modulation of E-cadherin expression and downregulation of ß-catenin signaling in hormone refractory PC-3 prostate cancer cells.

Elevated levels of insulin-like growth factor-1 (IGF-1) are associated with an increased risk of several different cancers, including prostate cancer. Inhibition of IGF-1 and the downstream signaling pathways mediated by the activation of the IGF-1 receptor (IGF-1R) may be involved in inhibiting prostate carcinogenesis. We investigated whether genistein downregulated the IGF-1/IGF-1R signaling pathway and inhibited cell growth in hormone refractory PC-3 prostate cancer cells. Genistein treatment caused a significant inhibition of IGF-1-stimulated cell growth. Flow cytometry analysis revealed that genistein significantly decreased the number of IGF-1-stimulated cells in the G0/G1 phase of the cell cycle. In IGF-1-treated cells, genistein effectively inhibited the phosphorylation of IGF-1R and the phosphorylation of its downstream targets, such as Src, Akt, and glycogen synthase kinase-3ß (GSk-3ß). IGF-1 treatment decreased the levels of E-cadherin but increased the levels of ß-catenin and cyclin D1. However, genistein treatment greatly attenuated IGF-1-induced ß-catenin signaling that correlated with increasing the levels of E-cadherin and decreasing cyclin D1 levels in PC-3 cells. In addition, genistein inhibited T-cell factor/lymphoid enhancer factor (TCF/LEF)-dependent transcriptional activity. These results showed that genistein effectively inhibited cell growth in IGF-1-stimulated PC-3 cells, possibly by inhibiting downstream of IGF-1R activation.

Inhibition of inflammation and carcinogenesis in the lung and colon by tocopherols.

Tocopherols, which exist in alpha, beta, gamma, and delta forms, are antioxidative nutrients also known as vitamin E. Although alpha-tocopherol (alpha-T) is the major form of vitamin E found in the blood and tissues, gamma- and delta-T have been suggested to have stronger anti-inflammatory activities. In the present study, using a tocopherol mixture that is rich in gamma-T (gamma-TmT, which contains 57%gamma-T), we demonstrated the inhibition of inflammation as well as of cancer formation and growth in the lung and colon in animal models. When given in the diet at 0.3%, gamma-TmT inhibited chemically induced lung tumorigenesis in the A/J mice as well as the growth of human lung cancer cell H1299 xenograft tumors. gamma-TmT also decreased the levels of 8-hydroxydeoxyguanosine, gamma-H2AX, and nitrotyrosine in tumors. More evident anti-inflammatory and cancer preventive activities of dietary gamma-TmT were demonstrated in mice treated with azoxymethane and dextran sulfate sodium. These results demonstrate the antioxidative, anti-inflammatory, and anticarcinogenic activities of tocopherols.

Analysis of multiple metabolites of tocopherols and tocotrienols in mice and humans.

Tocopherols and tocotrienols, collectively known as vitamin E, are essential antioxidant nutrients. The biological fates and metabolite profiles of the different forms are not clearly understood. The objective of this study is to simultaneously analyze the metabolites of different tocopherols and tocotrienols in mouse and human samples. Using HPLC/electrochemical detection and mass spectrometry, 18 tocopherol-derived and 24 tocotrienol-derived side-chain degradation metabolites were identified in fecal samples. Short-chain degradation metabolites, in particular gamma- and delta-carboxyethyl hydroxychromans (CEHCs) and carboxymethylbutyl hydroxychromans (CMBHCs) were detected in urine, serum, and liver samples, with tocopherols additionally detected in serum and liver samples. The metabolite profiles of tocotrienols and tocopherols were similar, but new tocotrienol metabolites with double bonds were identified. This is the first comprehensive report describing simultaneous analysis of different side-chain metabolites of tocopherols and tocotrienols in mice and humans. Urinary metabolites may serve as useful biomarkers for the nutritional assessment of vitamin E.

Hepatotoxicity of high oral dose (-)-epigallocatechin-3-gallate in mice.

The tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) has been studied for chronic disease preventive effects, and is marketed as part of many dietary supplements. However, case-reports have associated the use of green tea-based supplements with liver toxicity. We studied the hepatotoxic effects of high dose EGCG in male CF-1 mice. A single dose of EGCG (1500 mg/kg, i.g.) increased plasma alanine aminotransferase (ALT) by 138-fold and reduced survival by 85%. Once-daily dosing with EGCG increased hepatotoxic response. Plasma ALT levels were increased 184-fold following two once-daily doses of 750 mg/kg, i.g. EGCG. Moderate to severe hepatic necrosis was observed following treatment with EGCG. EGCG hepatotoxicity was associated with oxidative stress including increased hepatic lipid peroxidation (5-fold increase), plasma 8-isoprostane (9.5-fold increase) and increased hepatic metallothionein and gamma-histone 2AX protein expression. EGCG also increased plasma interleukin-6 and monocyte chemoattractant protein-1. Our results indicate that higher bolus doses of EGCG are hepatotoxic to mice. Further studies on the dose-dependent hepatotoxic effects of EGCG and the underlying mechanisms are important given the increasing use of green tea dietary supplements, which may deliver much higher plasma and tissue concentrations of EGCG than tea beverages.

Cancer-preventive activities of tocopherols and tocotrienols.

The cancer-preventive activity of vitamin E has been studied. Whereas some epidemiological studies have suggested a protective effect of vitamin E against cancer formation, many large-scale intervention studies with alpha-tocopherol (usually large doses) have not demonstrated a cancer-preventive effect. Studies on alpha-tocopherol in animal models also have not demonstrated robust cancer prevention effects. One possible explanation for the lack of demonstrable cancer-preventive effects is that high doses of alpha-tocopherol decrease the blood and tissue levels of delta-tocopherols. It has been suggested that gamma-tocopherol, due to its strong anti-inflammatory and other activities, may be the more effective form of vitamin E in cancer prevention. Our recent results have demonstrated that a gamma-tocopherol-rich mixture of tocopherols inhibits colon, prostate, mammary and lung tumorigenesis in animal models, suggesting that this mixture may have a high potential for applications in the prevention of human cancer. In this review, we discuss biochemical properties of tocopherols, results of possible cancer-preventive effects in humans and animal models and possible mechanisms involved in the inhibition of carcinogenesis. Based on this information, we propose that a gamma-tocopherol-rich mixture of tocopherols is a very promising cancer-preventive agent and warrants extensive future research.

Mixed tocopherols prevent mammary tumorigenesis by inhibiting estrogen action and activating PPAR-gamma.

PURPOSE: Tocopherols are lipophilic antioxidants present in vegetable oils. Although the antioxidant and anticancer activities of alpha-tocopherol (vitamin E) have been studied for decades, recent intervention studies with alpha-tocopherol have been negative for protection from cancer in humans. The tocopherols consist of four isoforms, which are the alpha, beta, gamma, and delta variants, and recent attention is being given to other isoforms. In the present study, we investigated the inhibitory effect of a tocopherol mixture rich in gamma- and delta-tocopherols against mammary tumorigenesis. EXPERIMENTAL DESIGN: Female Sprague Dawley rats were treated with N-methyl-N-nitrosourea (NMU), and then fed diets containing 0.1%, 0.3%, or 0.5% mixed tocopherols rich in gamma- and delta-tocopherols for 9 weeks. Tumor burden and multiplicity were determined, and the levels of markers of inflammation, proliferation, and apoptosis were evaluated in the serum and in mammary tumors. The regulation of nuclear receptor signaling by tocopherols was studied in mammary tumors and in breast cancer cells. RESULTS: Dietary administration of 0.1%, 0.3%, or 0.5% mixed tocopherols suppressed mammary tumor growth by 38%, 50%, or 80%, respectively. Tumor multiplicity was also significantly reduced in all three mixed tocopherol groups. Mixed tocopherols increased the expression of p21, p27, caspase-3, and peroxisome proliferator activated receptor-gamma, and inhibited AKT and estrogen signaling in mammary tumors. Our mechanistic study found that gamma- and delta-tocopherols, but not alpha-tocopherol, activated peroxisome proliferator activated receptor-gamma and antagonized estrogen action in breast cancer. CONCLUSION: The results suggest that gamma- and delta-tocopherols may be effective agents for the prevention of breast cancer.

Inhibition of lung cancer growth in mice by dietary mixed tocopherols.

Tocopherols are lipophilic antioxidants found in vegetable oils. Here, we examined the growth inhibitory effect of a gamma-tocopherol-enriched tocopherol mixture (gammaTmT) against CL13 murine lung cancer cells grown in culture and as subcutaneous tumors in A/J mice. We found gammaTmT had no effect after 2 days and weakly inhibited the growth of CL13 in culture after 5 days (28% growth inhibition at 80 microM). Dietary treatment with 0.1 and 0.3% gammaTmT for 50 days inhibited the growth of CL13 tumors in A/J mice by 53.9 and 80.5%, respectively. Histopathological analysis revealed an increase in tumor necrosis compared to control tumors (80 and 240% increase by 0.1 and 0.3% gammaTmT, respectively). Dietary treatment with gammaTmT dose-dependently increased gamma- (10.0-37.6-fold) and delta-tocopherol (8.9-26.7-fold) in the tumors of treated mice compared to controls. Dietary treatment with gammaTmT also increased plasma gamma- (5.4-6.7-fold) and delta-tocopherol (5.5-7-fold). Whereas others have demonstrated the cancer preventive activity of gammaTmT against mammary and colon cancer, this is the first report of growth inhibitory activity against lung cancer. Further studies are needed to determine the underlying mechanisms for this anticancer activity, and to determine if such activity occurs in other models of cancer.

A gamma-tocopherol-rich mixture of tocopherols inhibits colon inflammation and carcinogenesis in azoxymethane and dextran sulfate sodium-treated mice.

We investigated the effects of a gamma-tocopherol-rich mixture of tocopherols (gamma-TmT, containing 57% gamma-T, 24% delta-T, and 13% alpha-T) on colon carcinogenesis in azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated mice. In experiment 1, 6-week-old male CF-1 mice were given a dose of AOM (10 mg/kg body weight, i.p.), and 1 week later, 1.5% DSS in drinking water for 1 week. The mice were maintained on either a gamma-TmT (0.3%)-enriched or a standard AIN93M diet, starting 1 week before the AOM injection, until the termination of experiment. In the AOM/DSS-treated mice, dietary gamma-TmT treatment resulted in a significantly lower colon inflammation index (52% of the control) on day 7 and number of colon adenomas (9% of the control) on week 7. gamma-TmT treatment also resulted in higher apoptotic index in adenomas, lower prostaglandin E2, leukotriene B4, and nitrotyrosine levels in the colon, and lower prostaglandin E2, leukotriene B4, and 8-isoprostane levels in the plasma on week 7. Some of the decreases were observed even on day 7. In experiment 2 with AOM/DSS- treated mice sacrificed on week 21, dietary 0.17% or 0.3% gamma-TmT treatment, starting 1 week before the AOM injection, significantly inhibited adenocarcinoma and adenoma formation in the colon (to 17-33% of the control). Dietary 0.3% gamma-TmT that was initiated after DSS treatment also exhibited a similar inhibitory activity. The present study showed that gamma-TmT effectively inhibited colon carcinogenesis in AOM/DSS-treated mice, and the inhibition may be due to the apoptosis-inducing, anti-inflammatory, antioxidative, and reactive nitrogen species-trapping activities of tocopherols.

Voluntary exercise inhibits intestinal tumorigenesis in Apc(Min/+) mice and azoxymethane/dextran sulfate sodium-treated mice.

BACKGROUND: Epidemiological studies suggest that physical activity reduces the risk of colon cancer in humans. Results from animal studies, however, are inconclusive. The present study investigated the effects of voluntary exercise on intestinal tumor formation in two different animal models, Apc(Min/+) mice and azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated mice. METHODS: In Experiments 1 and 2, five-week old female Apc(Min/+) mice were either housed in regular cages or cages equipped with a running wheel for 6 weeks (for mice maintained on the AIN93G diet; Experiment 1) or 9 weeks (for mice on a high-fat diet; Experiment 2). In Experiment 3, male CF-1 mice at 6 weeks of age were given a dose of AOM (10 mg/kg body weight, i.p.) and, 12 days later, 1.5% DSS in drinking fluid for 1 week. The mice were then maintained on a high-fat diet and housed in regular cages or cages equipped with a running wheel for 16 weeks. RESULTS: In the Apc(Min/+) mice maintained on either the AIN93G or the high-fat diet, voluntary exercise decreased the number of small intestinal tumors. In the AOM/DSS-treated mice maintained on a high-fat diet, voluntary exercise also decreased the number of colon tumors. In Apc(Min/+) mice, voluntary exercise decreased the ratio of serum insulin like growth factor (IGF)-1 to IGF binding protein (BP)-3 levels. It also decreased prostaglandin E2 and nuclear beta-catenin levels, but increased E-cadherin levels in the tumors. CONCLUSION: These results indicate hat voluntary exercise inhibited intestinal tumorigenesis in Apc(Min/+) mice and AOM/DSS-treated mice, and the inhibitory effect is associated with decreased IGF-1/IGFBP-3 ratio, aberrant beta-catenin signaling, and arachidonic acid metabolism.