Barbara C. Pence

Selenium compounds have disparate abilities to impose oxidative stress and induce apoptosis.

The cancer chemopreventive effect of selenium cannot be fully accounted for by the role of selenium as a component of the antioxidant enzyme glutathione peroxidase, which suggests that chemoprevention occurs by another mechanism. Several studies have shown that thiol oxidation and free radical generation occur as a consequence of selenium catalysis and toxicity. In the present study, we evaluated three different selenium compounds; selenite, selenocystamine, and selenomethionine to determine the relative importance of the prooxidative effects of these compounds with regard to their ability to induce apoptosis. The experimental results suggest that, in addition to supporting an increased activity of glutathione peroxidase, an antioxidant function that the three selenium compounds did with equal efficacy, catalytic selenite, and selenocystamine generated 8-hydroxydeoxyguanosine DNA adducts, induced apoptosis and were found to be cytotoxic in mouse keratinocytes. The noncatalytic selenomethionine was not cytotoxic, did not generate 8-hydroxydeoxyguanosine adducts and did not induce cellular apoptosis at any of the selenium concentrations studied. In keratinocytes, apoptosis may be initiated by superoxide (O2*-) and oxidative free radicals that are generated by selenite and selenocystamine, but not by selenomethionine.

Induction of differentiation and apoptosis by sodium selenite in human colonic carcinoma cells (HT29)

To explore the mechanism(s) by which selenium (Se) exerts its cancer chemopreventive activity, we studied the effect of selenite (0-100 microM) on cell growth, viability, differentiation, detachment, DNA fragmentation and apoptosis in human colonic carcinoma cells (HT29). Selenite (>5 microM) decreased cell growth, increased cell detachment and decreased intracellular levels of reduced glutathione (GSH), whereas >10 microM selenite induced cell differentiation and apoptosis. The chemopreventive effects of selenite may be related in part to the generation of reactive oxygen species (ROS) resulting from the reaction between selenite and GSH.

Green tea polyphenols supplementation and Tai Chi exercise for postmenopausal osteopenic women: safety and quality of life report

BackgroundEvidence suggests that both green tea polyphenols (GTP) and Tai Chi (TC) exercise may benefit bone health in osteopenic women. However, their safety in this population has never been systematically investigated. In particular, there have been hepatotoxicity concerns related to green tea extract. This study was to evaluate the safety of 24 weeks of GTP supplementation combined with TC exercise in postmenopausal osteopenic women, along with effects on quality of life in this population.Methods171 postmenopausal women with osteopenia were randomly assigned to 4 treatment arms for 24 weeks: (1) Placebo (500 mg starch/day), (2) GTP (500 mg GTP/day), (3) Placebo + TC (placebo plus TC training at 60 min/session, 3 sessions/week), and (4) GTP + TC (GTP plus TC training). Safety was examined by assessing liver enzymes (aspartate aminotransferase, alanine aminotransferase), alkaline phosphatase, and total bilirubin at baseline and every 4 weeks. Kidney function (urea nitrogen and creatinine), calcium, and inorganic phosphorus were also assessed at the same times. Qualify of life using SF-36 questionnaire was evaluated at baseline, 12, and 24 weeks. A mixed model of repeated measures ANOVA was applied for analysis.Results150 subjects completed the study (12% attrition rate). The compliance rates for study agents and TC exercise were 89% and 83%, respectively. Neither GTP supplementation nor TC exercise affected liver or kidney function parameters throughout the study. No adverse event due to study treatment was reported by the participants. TC exercise significantly improved the scores for role-emotional and mental health of subjects, while no effect on quality of life was observed due to GTP supplementation.ConclusionsGTP at a dose of 500 mg/day and/or TC exercise at 3 hr/week for 24 weeks appear to be safe in postmenopausal osteopenic women, particularly in terms of liver and kidney functions. TC exercise for 24 weeks (3 hr/wk) significantly improved quality of life in terms of role-emotional and mental health in these subjects. ClinicalTrials.gov identifier: NCT00625391.

Feeding of a well‐cooked beef diet containing a high heterocyclic amine content enhances colon and stomach carcinogenesis in 1,2‐dimethylhydrazine‐treated rats

Epidemiologic studies have linked the consumption of red meat and the consumption of highly browned meats containing high levels of heterocyclic aromatic amines (HCAs) to increased risk of colorectal cancer or polyps. The present study determined the effects of long-term feeding of beef-containing diets with low and high levels of HCAs (in the context of a low or high beef tallow diet) on a standard 1,2-dimethylhydrazine (DMH)-induced colon tumorigenesis protocol. Very lean beef was cooked by a variety of methods at different temperatures, and the levels of the major HCAs (2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline, and 2-amino-1-methyl-6-phenylimidazo[4,5-f]pyridine) were measured by high-performance liquid chromatography. Diets incorporating beef containing low or high levels of HCAs were fed for 12 weeks, during which DMH was administered to induce colon tumors, followed by various dietary regimens as promotional stimuli. Feeding of a beef diet high in HCAs resulted in more DMH-induced colon adenocarcinomas, but only in the context of a low-fat diet. The high-HCA diets increased stomach tumors in all DMH-treated rats. An apparent interaction of high HCA with a high fat level reduced the colon tumor incidence and tumor numbers in those diets containing both factors. These results support the epidemiologic data linking well-cooked meat to increased risk for colon and stomach cancer, but the role of dietary fat level remains puzzling.

Diet, Nutrition, and Cancer Prevention

C.S. Yang opened the workshop by welcoming the participants, and he stated the purposes of the workshop. Research on diet, nutrition and cancer prevention is recognized as an important area of research, yet this area of research is not well funded. The purpose of the workshop is to strengthen this area of research by discussing how to select more relevant problems, develop attractive hypotheses, and use effective approaches to obtain research aims. Other important tasks are to convey the importance of the research and to increase the funding in the area of diet and cancer prevention. A proposed outline of discussion for the workshop was presented (Appendix 1).

Non-promoting effects of iron from beef in the rat colon carcinogenesis model

Significant alarm has existed among the general public in the past few years that eating red meat may cause human colon cancer. Iron in beef has been hypothesized as one of the factors in the etiology of this cancer. The present study was designed to test the hypothesis that dietary iron solely from beef would enhance colon tumorigenesis induced in rats. Tumors were induced in Sprague-Dawley rats with 1,2-dimethylhydrazine (20 mg/kg body weight for 10 weeks). Seventy male weanling rats were randomized to two dietary treatment groups with two iron sources (very lean beef vs. iron citrate) as the factor. The rats were allowed free access to the respective diet and deionized water for 27 weeks. At termination of the study, the rats were examined for location, size and type of colon or extracolonic lesions. No significant differences were found in total incidence and number of colon tumors between the beef (51.7%, 0.8 tumors/rat) and casein (62.1%, 0.9 tumors/rat) diets, although the serum iron levels of rats fed the beef diet were higher than for those fed the casein diet. The results demonstrate that, when lean beef is used as an iron source, the risk for colon carcinogenesis is not increased.

Mitigation of Oxidative Damage by Green Tea Polyphenols and Tai Chi Exercise in Postmenopausal Women with Osteopenia

Background Osteoporosis is a degenerative bone disease predominantly in postmenopausal women. Green tea polyphenols (GTP) and Tai Chi (TC) have been shown to be beneficial on human bone health. This study examined the efficacy of GTP and TC on mitigation of oxidative damage in postmenopausal women with osteopenia. Methods A 6-month randomized and placebo-controlled clinical trial was conducted in 171 postmenopausal women with osteopenia, who were recruited from Lubbock County, Texas. These participants were treated with placebo, GTP (500 mg daily), placebo + TC (60-minute group exercise, 3 times/week), or GTP (500 mg daily) + TC (60-minute group exercise, 3 times/week), respectively. Their blood and urine samples were collected at the baseline, 1-, 3- and 6-months during intervention for assessing levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), an oxidative DNA damage biomarker, and concentrations of serum and urine GTP components. Results The elevated concentrations of serum and urinary GTP components demonstrated a good adherence for the trial. A significant reduction of urinary 8-OHdG concentrations was found in all three treated groups during 3-month (P<0.001) and 6-month (P<0.001) intervention, as compared to the placebo group. The significant time- and dose-effects on mitigation of the oxidative damage biomarker were also found for GTP, TC, and GTP+TC intervened groups. Conclusion Our study demonstrated that GTP and TC interventions were effective strategies of reducing the levels of oxidative stress, a putative mechanism for osteoporosis in postmenopausal women, and more importantly, working in an additive manner, which holds the potential as alternative tools to improve bone health in this population. Trial Registration ClinicalTrials.gov NCT00625391

Inhibition of selenite-induced cytotoxicity and apoptosis in human colonic carcinoma (HT-29) cells by copper

Selenite catalytically oxidizes reduced glutathione (GSH) with subsequent generation of superoxide. Our laboratory has previously shown that this selenite-catalyzed generation of superoxide is strongly inhibited by copper [as copper(II) sulfate]. In the present study we have demonstrated that exposure of human colonic carcinoma cells (HT-29) to selenite resulted in the induction of apoptosis, DNA fragmentation, an increase in intracellular levels of the antioxidant GSH, and cytotoxicity. Selenite-induced apoptosis, DNA fragmentation, increases in GSH levels, and cytotoxicity were inhibited by copper(II) sulfate. Copper only protected cells from selenite cytotoxicity when cells were exposed to selenite and copper simultaneously, not when cells were pretreated with copper, then washed before selenite exposure. This suggests that copper elicits its protective effect extracellularly. Previous data reported by this laboratory clearly demonstrated that copper inhibited selenite-catalyzed superoxide generation. Collectively, these data suggest that reactive oxygen species may play a role in selenite-induced cytotoxicity, apoptosis, and DNA fragmentation.

Protective effects of calcium from nonfat dried milk against colon carcinogenesis in rats

A number of studies have demonstrated the protective effect of dietary calcium against risk for colon cancer. The objective of this experimental study was to test the efficacy of two sources of dietary calcium, elemental calcium in the form of CaCO3 and dairy calcium as nonfat dried milk (NFDM), in colon tumor inhibition. Male weanling F344 rats were fed six test diets containing low (LF, 5%) and high (HF, 20%) levels of corn oil and low (0.5%) and high (1.0%) levels of calcium supplemented as CaCO3 or NFDM in a 2 x 3 factorial design. Tumors were induced with two weekly injections of azoxymethane at 12 mg/kg body wt. After 27 weeks on the test diets, animals were necropsied for tumor analysis. There was no difference in tumor incidence for fat or calcium source main effects, but a significant interaction was seen between fat and calcium source, with the lowest tumor incidence seen in the HF/NFDM group. Calcium compartmentalization studies demonstrated no effects of calcium on serum calcium levels but increased urinary and fecal water calcium in the higher-calcium diets. Increased dietary calcium also decreased fecal bile acid concentrations, but there was no effect on fecal water bile acids. Intermediate biomarkers of colon carcinogenesis were not affected by the dietary treatments except for fat effects on carcinogen-induced nuclear aberrations. These results indicate that source of calcium is not critical but that total dietary context may affect efficacy of calcium against colon carcinogenesis.

Effects of dietary fat and 1,2-dimethylhydrazine on microsomal lipid peroxidation

Abstract An increased intake of polyunsaturated fatty acids, especially those of the omega-3 series, has shown beneficial effects in prevention of chronic diseases, including cancer. It is not known if at high levels, incorporation of these fatty acids into membrane phospholipids will cause adverse effects due to increased tissue susceptibility to peroxidation. This study was designed to determine whether diets high in polyunsaturated fatty acids would increase liver and colon susceptibility to peroxidation. Secondly, the study examined the effect of diet and the colon carcinogen, 1,2-diemethylhydrazine, on potential peroxidation in these tissues. Rats were fed diets of varied fatty acid composition and effects were compared over time and as the result of injection of 1,2-dimethylhydrazine. Test diets consisted of a low fat corn oil diet or high fat diets of either corn oil, beef tallow, or menhaden oil. Fatty acid composition of colon microsomes was determined. Lipid peroxidation products were measured as thiobarbituric acid-reacting substances in liver and colon microsomes before and after induction with iron/ADP/ascorbate. Content of polyunsaturated fatty acids in colon microsomes was shown to vary according to diet. Induced peroxidation of liver microsomes was highest in the menhaden oil group but only in young animals. Older animals showed greater levels of induced peroxidation in the liver and less effect of diet. Dimethylhydrazine increased inducible peroxidation in the liver without a clear pattern of difference by diet. Tissue differences were also apparent. Colon microsomes showed resistance to peroxide induction by iron/ADP/ascorbate and no difference in peroxide content as the result of DMH. Increases in lipid peroxidation do not appear to be associated with this model of colon carcinogenesis.