Chemopreventive effect of carvacrol on 1,2-dimethylhydrazine induced experimental colon carcinogenesis.

PURPOSE: Colorectal cancer (CRC) is a leading cause for cancer-related death and its prevention is of great importance throughout the world. Chemoprevention offers a novel approach to control the incidence of colon cancer. The present study was performed to evaluate the efficacy of carvacrol supplementation on colonic aberrant crypt foci (ACF), lipid peroxidation, and antioxidant defense system in 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in male Wistar rats. MATERIALS AND METHODS: The rats were randomly divided into six groups. Group 1, control rats received modified pellet diet; Group 2 rats received modified pellet diet along with carvacrol (80 mg/kg b.wt/day); Groups 3-6 received subcutaneous injection of DMH (20 mg/kg b.wt), once a week for the first 4 weeks; in addition Groups 4-6 received carvacrol at three different doses of 20, 40, and 80 mg/kg b.wt/day for 16 weeks. RESULTS: Our result suggest that increased tumor incidence and increased number of ACF, increased bacterial enzymes accompanied by a decrease in the colonic lipid peroxidation, glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) activities were observed in DMH-treated rats. Administration of carvacrol to DMH-treated rats significantly decreased the tumor incidence and the number of ACF and bacterial enzymes with enhancement of colonic lipid peroxidation, GPx, SOD, and CAT activities. CONCLUSION: The results of this study suggest that carvacrol at a dose of 40 mg/kg b.wt showed a significant beneficial effect against chemically-induced colon carcinogenesis in rats.

Rosmarinic acid inhibits DMH-induced cell proliferation in experimental rats.

BACKGROUND: Colon cancer is one of the most common cancers in both men and women. The present study is an effort to unravel the anticarcinogenic effects of rosmarinic acid (RA) in 1,2-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. Administration of DMH induces multiple tumors in the rat colon, which mimics human colon cancer. METHODS: Male Wistar rats were divided into six groups and fed a high-fat diet. Group 1 served as control, group 2 rats were given RA [5 mg/kg body weight (b.w.)] orally every day for a total period of 30 weeks, and groups 3-6 were given weekly injections of DMH (20 mg/kg b.w. subcutaneous) once a week in the groin for the first 15 weeks. In addition to DMH, groups 4-6 received RA at a dose of 5 mg/kg b.w. during the initiation and postinitiation stages, and also throughout the entire study period. Colon tissues were examined histologically; further, the extent of oxidative stress was assessed by measuring lipid peroxidation and antioxidant levels in the colonic mucosa of rats. RESULTS: Macroscopic and microscopic tumors were identified in all the groups that received DMH. The results revealed that supplementation with RA significantly inhibited the tumor formation and tumor multiplicity in DMH-treated rats. RA supplementation to DMH-administered rats significantly reduced the cell proliferation markers, namely, argyrophilic nucleolar organizing regions as well as proliferative cell nuclear antigen labeling index. In addition, RA supplementation reduces the expressions of tumor necrosis factor-α, interlukin-6, and cyclooxygenase-2, and modulates the expression of p65. CONCLUSIONS: The above findings clearly underline the chemopreventive efficacy of RA against DMH-induced colon carcinogenesis.

Modulatory effect of troxerutin on biotransforming enzymes and preneoplasic lesions induced by 1,2-dimethylhydrazine in rat colon carcinogenesis.

Colon cancer is the third most global oncologic problem faced by medical fraternity. Troxerutin, a flavonoid present in tea, coffee, cereal grains, and a variety of fruits and vegetables, exhibits various pharmacological and biological activities. This study was carried out to investigate the effect of troxerutin on xenobiotic metabolizing enzymes, colonic bacterial enzymes and the development of aberrant crypt foci (ACF) during 1,2-dimethylhydrazine (DMH) induced experimental rat colon carcinogenesis. Male albino Wistar rats were randomly divided into six groups. Group 1 served as control. Group 2 received troxerutin (50 mg/kg b.w., p.o. every day) for 16 weeks. Groups 3-6 received subcutaneous injections of DMH (20 mg/kg b.w.) once a week, for the first four weeks. In addition, groups 4-6 received different doses of troxerutin (12.5, 25, 50 mg/kg b.w., p.o. every day respectively) along with DMH injections. Our results reveal that DMH treated rats exhibited elevated activities of phase I enzymes such as cytochrome P450, cytochrome b5, cytochrome P4502E1, NADPH-cytochrome P450 reductase and NADH-cytochrome b5 reductase and reduced activities of phase II enzymes such as glutathione-S-transferase (GST), DT-diaphorase (DTD) and uridine diphospho glucuronyl transferase (UDPGT) in the liver and colonic mucosa of control and experimental rats. Furthermore, the activities of fecal and colonic mucosal bacterial enzymes, such as ß-glucronidase, ß-glucosidase, ß-galactosidase and mucinase were found to be significantly higher in DMH alone treated rats than those of the control rats. On supplementation with troxerutin to DMH treated rats, the alterations in the activities of the biotransforming enzymes, bacterial enzymes and the pathological changes were significantly reversed, the effect being more pronounced when troxerutin was supplemented at the dose of 25 mg/kg b.w. Thus troxerutin could be considered as a good chemopreventive agent against the formation of preneoplastic lesions in a rat model of colon carcinogenesis.

Chemopreventive effect of zingerone against colon carcinogenesis induced by 1,2-dimethylhydrazine in rats.

Zingerone [4-(4-hydroxy-3-methoxyphenyl)-2-butane], one of the active phenolic components isolated from Zingiber officinale, has antioxidant and anticarcinogenic properties. In our study, we have evaluated the effect of different doses of zingerone on lipid peroxidation (thiobarbituric acid-reactive substances, lipid hydroxyl radical and conjugated dienes), tissue enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase), and nonenzymatic antioxidants (reduced glutathione, vitamin E, vitamin C), and also the formation of aberrant crypt foci (ACF) in male albino Wistar rats with colon cancer induced using 1,2-dimethylhydrazine (DMH). The rats were divided into six groups. Group 1 served as a control group and received a modified pellet diet; the rats in group 2 received a modified pellet diet along with zingerone (40 mg/kg b.w., orally every day); groups 3-6 were administered DMH (20 mg/kg b.w., subcutaneously) once a week for the first 4 weeks; and groups 4-6 received zingerone at three different doses of 10, 20 and 40 mg/kg b.w., respectively, every day for 16 weeks. Increased tumour incidence and ACF formation were accompanied by a decrease in the tissue lipid peroxidation, enzymatic and nonenzymatic antioxidant activities observed in the colon of DMH-treated rats. Supplementation with zingerone in DMH-treated rats led to a significant decrease in the tumour incidence and ACF formation with simultaneous modulation in the level of tissue lipid peroxidation and antioxidant status. Thus, in conclusion, we can suggest that zingerone effectively inhibits DMH-induced colon carcinogenesis in male Wistar rats.

Antiproliferative efficacy of hesperetin (citrus flavanoid) in 1,2-dimethylhydrazine-induced colon cancer.

Cancer is the second leading cause of death worldwide and is increasing at an alarming rate. The present study was to evaluate the antiproliferative effects of hesperetin, a flavonoid commonly found in many herbal medicines and foods, on aberrant crypt foci (ACF), argyrophylic nucleolar organizer regions (AgNORs) and proliferating cell nuclear antigen (PCNA) in 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rats. Rats were given subcutaneous injections of DMH (20 mg/kg body weight) weekly for 15 weeks to induce carcinogenesis, and hesperetin was administered orally at the dose of 20 mg/kg body weight. DMH exposure alone produced a high incidence of ACF and showed positive staining for PCNA and AgNORs in colonic tissues. Supplementation with hesperetin lowered the PCNA labeling index and suppressed the formation of ACF in the rats with colon cancer. These results clearly reveal that dietary hesperetin possesses antiproliferative ability against chemically induced colon tumourigenesis.

Colon cancer chemopreventive efficacy of silibinin through perturbation of xenobiotic metabolizing enzymes in experimental rats.

Our findings reported so far demonstrate that silibinin modulates gut microbial enzymes, colonic oxidative stress and Wnt/ß-catenin signaling, to exert its antiproliferative effect against 1,2 di-methylhydrazine (DMH) induced colon carcinogenesis. Since xenobiotic metabolizing enzymes play a crucial role in carcinogen activation and metabolism, we aimed to explore the effect of silibinin on xenobiotic metabolizing enzymes during DMH induced colon carcinogenesis. Male albino rats were randomly divided into six groups. Group 1 served as control and group 2 rats received 50mg/kg body weight of silibinin p.o. every day. Groups 3-6 rats were given DMH at a dose of (20mg/kg body weight subcutaneously) once a week for 15 weeks to induce colonic tumors. In addition to DMH, group 4 (initiation), group 5 (post-initiation) and group 6 (entire period) rats received silibinin (50mg/kg body weight, p.o., everyday) at different time points during the experimental period of 32 weeks. Rats exposed to DMH alone showed increased activities of phase I enzymes (cytochrome b5, cytochrome b5 reductase, cytochromeP450, cytochromeP450 reductase, cytochromP4502E1) and decreased activities of phase II enzymes (Uridine diphospho glucuronyl transferase, Glutathione-S-transferase and DT-Diaphorase) in the liver and colonic mucosa as compared to control rats. Silibinin supplementation modulates the xenobiotic metabolizing enzymes favoring carcinogen detoxification. Evaluation of lipid peroxidation and antioxidants status showed that silibinin supplementation counteracts DMH induced hepatic and circulatory oxidative stress. Tumor burden in experimental animals was assessed both macroscopically and microscopically in the colon tissues. Our findings emphasize the potential chemopreventive action of silibinin against DMH induced colon carcinogenesis.

Dietary d-limonene alleviates insulin resistance and oxidative stress-induced liver injury in high-fat diet and L-NAME-treated rats.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is one of the most common etiologies of chronic liver disease worldwide. The pathogenesis of metabolic syndrome associated with NAFLD is still under debate. AIM OF THE SCOPE: This study has investigated the hepatic biochemical and histological changes and also insulin resistance in metabolic syndrome associated with NAFLD. METHODS: Young male Wistar rats fed a high-fat diet (HFD 42.2% beef tallow) together with N ( ω )-nitro-L-arginine methyl ester (L-NAME; 80 mg/L in drinking water) for 8 weeks and subsequently with 2% d-limonene for the final 4 weeks. RESULTS: HFD-fed rats treated with L-NAME showed increased systolic blood pressure, heart rate, fasting blood glucose, plasma insulin, hepatic marker enzymes, hepatic lipids, circulatory lipid peroxidation by-products, and hepatic phase I enzyme activities with decreased circulatory nonenzymic antioxidant concentrations and hepatic phase II enzyme activities. Dietary supplementation with d-limonene reversed the HFD and L-NAME-induced changes and restored pathological alteration of liver and pancreas. CONCLUSIONS: These data provide new insights into the therapeutic approach of d-limonene against the development of the metabolic syndrome associated with NAFLD.

Role of hesperetin (a natural flavonoid) and its analogue on apoptosis in HT-29 human colon adenocarcinoma cell line--a comparative study.

Colon cancer is one of the serious health problems in most developed countries and its incidence rate is increasing in India. Hesperetin (HN) (3',5,7-trihydroxy-4'-methoxyflavonone) and hesperetin analogue (HA) were tested for their apoptosis inducing ability. Methyl thiazolyl tetrazolium assay revealed a dose as well as duration-dependent reduction of HT-29 (colon adenocarcinoma) cellular growth in response to HN and HA treatment. At 24 h 70 µM of HN and 32 µM of HA showed 50% reduction of HT-29 cellular growth. Acridine orange/ethidium bromide staining showed apoptotic features of cell death induced by HN and HA. Rhodamine 123 staining showed significant reduction in mitochondrial membrane potential induced by HN and HA. HN and HA induced DNA damage was confirmed by comet tail formation. Lipid peroxidation markers (TBARS) and protein oxidation marker (PCC) were significantly elevated in HN and HA treated groups. Enzymic antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) were slightly decreased in their activities compared to control (untreated HT-29 cells). Results of Western blot analysis of apoptosis associated genes revealed an increase in cytochrome C, Bax, cleaved caspase-3 expression and a decrease in Bcl-2 expression. These findings indicate that HN and HA induce apoptosis on HT-29 via Bax dependent mitochondrial pathway involving oxidant/antioxidant imbalance.

What is new for an old molecule? Systematic review and recommendations on the use of resveratrol.

BACKGROUND: Resveratrol is a natural compound suggested to have beneficial health effects. However, people are consuming resveratrol for this reason without having the adequate scientific evidence for its effects in humans. Therefore, scientific valid recommendations concerning the human intake of resveratrol based on available published scientific data are necessary. Such recommendations were formulated after the Resveratrol 2010 conference, held in September 2010 in Helsingør, Denmark. METHODOLOGY: Literature search in databases as PUBMED and ISI Web of Science in combination with manual search was used to answer the following five questions: (1)Can resveratrol be recommended in the prevention or treatment of human diseases?; (2)Are there observed "side effects" caused by the intake of resveratrol in humans?; (3)What is the relevant dose of resveratrol?; (4)What valid data are available regarding an effect in various species of experimental animals?; (5)Which relevant (overall) mechanisms of action of resveratrol have been documented? CONCLUSIONS/SIGNIFICANCE: The overall conclusion is that the published evidence is not sufficiently strong to justify a recommendation for the administration of resveratrol to humans, beyond the dose which can be obtained from dietary sources. On the other hand, animal data are promising in prevention of various cancer types, coronary heart diseases and diabetes which strongly indicate the need for human clinical trials. Finally, we suggest directions for future research in resveratrol regarding its mechanism of action and its safety and toxicology in human subjects.

Dose response effect of rutin a dietary antioxidant on alcohol-induced prooxidant and antioxidant imbalance - a histopathologic study.

The present study was designed to investigate the effect of rutin on ethanol-induced hepatotoxicity in a dose-dependent manner in rats. Male albino rats were divided into six groups. Group 1 rats served as control and group 2 rats received rutin 100 mg/kg body weight. Hepatotoxicity was induced in groups 3-6 rats (20% ethanol) for 60 days. In addition, groups 4-6 rats received rutin at doses of 25, 50, 100 mg/kg body weight, respectively for the last 30 days of the experiment. We observed a significant increase in the activities of liver marker enzymes, serum amino transferases, alkaline phosphatase, γ-glutamyl transpeptidase the levels of thiobarbituric acid reactive substances, conjugated dienes, lipid hydroperoxides, and a decrease in the activities of superoxide dismutase (SOD), catalase (CAT), glutathione and its related enzymes, vitamins C and E when compared to ethanol-fed rats. Rutin supplementation along with ethanol significantly decreased the levels of liver marker enzymes, lipid peroxidation and significantly elevated the activities of liver SOD, CAT, GSH, glutathione peroxidase, vitamins C and E when compared to untreated ethanol supplemented rats. Among the three doses, 100 mg/kg body weight of rutin was found to exert a more pronounced hepatoprotective effect against ethanol-induced toxicity. Our results were also confirmed by the histopathologic observations.

Oral supplementation of silibinin prevents colon carcinogenesis in a long term preclinical model.

Chemoprevention through dietary intervention is an emerging option to reduce colon cancer mortality. beta-catenin plays an important role in the Wnt signaling cascade that is most commonly dysregulated in colorectal cancer. Our aim was to explore the modulatory effect of silibinin on beta-catenin expression employing 1,2-dimethylhydrazine (DMH) induced colon cancer in male Wistar rats as an experimental model during the different stages of carcinogenesis. Colon tissues were analyzed for the expression of beta-catenin, proliferating cell nuclear antigen (PCNA) and argyrophilic nucleolar organizer regions by using immunohistochemistry and silver staining. Immunoblotting was employed to study cyclin D1 expression. Glutathione (GSH) and glutathione related enzymes were assayed by spectrophotometric analysis. Silibinin inhibited DMH-induced colon cancer by decreasing tumor incidence and multiplicity. Silibinin supplementation to DMH-treated rats restored the levels of GSH-dependent enzymes and decreased the levels of beta-catenin, PCNA, argyrophilic nucleolar organizer regions and cyclin D1. Mechanistically silibinin inhibits DMH-induced colon carcinogenesis by modulating the Wnt/beta-catenin pathway and glutathione redox system. Since colon cancer is highly sensitive to dietary intervention adults who may have preneoplastic lesions in their colon may be benefited by silibinin.

Inhibitory effect of morin on DMH-induced biochemical changes and aberrant crypt foci formation in experimental colon carcinogenesis.

Morin is a flavonoid present in fruits and Chinese herbs, exhibits various beneficial biological activities. There are numerous evidence suggesting that total dietary fat intake is generally associated with early promotion of colon cancer, the alterations in the lipid profile is important for malignant transformation and tumor development and carbohydrate moieties of glycoproteins reflect the stage of cancer. Aberrant crypt foci (ACF) consisting of morphologically irregular crypts, are thought to be precancerous lesions for colon cancer. Our aim was to study the inhibitory effect morin on aberrant crypt foci and alterations in the levels of lipids, and glycoconjugates in experimental rat colon cancer. Group 1 served as control, groups 2 and 4 received 50mg/kg b.w. morin orally everyday for 30 weeks. Groups 3 and 4 were given subcutaneous injection of 1,2-dimethylhydrazine (DMH) 20mg/kg b.w. for the first 15 weeks. Administration of morin at the dose of 50mg/kg b.w., significantly suppressed the formation of ACF its multiplicity and lowered levels of serum and tissue lipids, cholesterol-phospholipid ratio, glycoconjugate and also increased the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase). These results indicate that morin has a protective effect against DMH-induced colon carcinogenesis.

Silibinin ameliorates oxidative stress induced aberrant crypt foci and lipid peroxidation in 1, 2 dimethylhydrazine induced rat colon cancer.

Pharmacological intervention to reduce CRC mortality entails the use of oral agents that can avert carcinogenesis. Silibinin, a major component of silymarin isolated from Silybum marianum (L.) was found to possess attractive remedial features. An in vivo study was designed to elucidate the effect of silibinin on the formation of 1, 2 dimethylhydrazine (DMH) induced aberrant crypt foci (ACF), tissue lipid peroxidation (LPO) and enzymic antioxidants status during different phases of experimental colon cancer. DMH alone treated rats showed significantly (p < 0.05) increased size and number of ACF, accompanied by decreased LPO and enzymic antioxidant activities. Administration of silibinin to DMH treated rats inhibited mean colonic ACF and multi-crypt AC/foci and also improved the levels of enzymic antioxidants in a time dependent manner. Histologically no obvious sign of neoplasia was observed in silibinin supplemented DMH treated rats during the various stages of carcinogenesis. Our results show that silibinin possesses potent chemopreventive activity against colon carcinogenesis.

Chemopreventive efficacy of gallic acid, an antioxidant and anticarcinogenic polyphenol, against 1,2-dimethyl hydrazine induced rat colon carcinogenesis.

Colon cancer is a major cause of morbidity and mortality in developed and developing countries and its etiology is known to be a combination of hereditary, environmental, dietary factors and lack of physical activity. Chemoprevention offers a novel approach to control the incidence of colon cancer. Gallic acid (GA) is a polyphenol widely present in tea and other plants which is popularly used in the traditional medicine of China. The present study was to evaluate the efficacy of GA supplementation on tissue lipid peroxidation and antioxidant defense system in 1,2-dimethyhydrazine (DMH) induced colon carcinogenesis in male Wistar rats. The rats were assorted into six groups, viz., group1 control rats received modified pellet diet; group 2 rats received GA (50 mg/kg body weight) orally along with modified pellet diet; group 3 rats received DMH (20 mg/kg body weight) subcutaneously once a week for the first 15 weeks; groups 4, 5 and 6 rats received GA along with DMH during the initiation, post- initiation stages and the entire period of study respectively. All the rats were sacrificed at the end of 30 weeks and the tissues were evaluated biochemically. We observed decreased lipid peroxidation (LPO) products such as thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH) and conjugated dienes (CD) and diminished levels of antioxidants such as superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), glutathione reductase (GR) and glutathione peroxidase (GPx) in the tissues of DMH treated rats, which were elevated significantly on GA supplementation. Moreover, enhanced activity of ascorbic acid and alpha-tocopherol levels were also observed in DMH alone treated rats which were significantly reduced on GA supplementation. Our results suggest that GA could exert a significant chemopreventive effect on DMH induced colon carcinogenesis.

Influence of dietary resveratrol on early and late molecular markers of 1,2-dimethylhydrazine-induced colon carcinogenesis.

OBJECTIVE: Colon cancer is an exceptionally aggressive disease, and the use of natural or synthetic substances to prevent or decrease cancer risk without adverse effects remains a major challenge. In this study, the mechanistic basis for the chemopreventive effect of resveratrol (Res) on 1,2-dimethylhydrazine-induced colon carcinogenesis in an rat model was evaluated. METHODS: Rats were randomized into six groups. Group 1 were control rats, group 2 were control rats that received Res (8mg/kg of body weight orally every day), and rats in groups 3-6 were treated once per week with 1,2-dimethylhydrazine (20mg/kg of body weight, subcutaenously, 15 times). In addition, groups 4-6 received Res (as in group 2) in three dietary regimens: initiation, postinitiation, and entire period. All rats were sacrificed after 30 wk and the degree of inflammation, cell proliferation, apoptosis, and mucosal integrity was evaluated. RESULTS: Res supplementation during the entire period significantly amended the expression of inflammatory, cell proliferative, and apoptotic biomarkers such as cyclo-oxygenase-2, ornithine decarboxylase, caspase-3, and heat shock proteins 70 and 27. Moreover, supplementing Res for the entire study period modulated the colonic mucosal protein mucin 1 and 2 expression. CONCLUSION: The results clearly indicate that chronic Res supplementation inhibited the colon cancer development through modulating the early and late events of carcinogenesis and helped to maintain the colonic mucosal integrity. Thus our study demonstrates that the chemopreventive efficacy of Res could be attributed to its action on multiple direct targets of carcinogenesis.

Silibinin modulates biotransforming microbial enzymes and prevents 1,2-dimethylhydrazine-induced preneoplastic changes in experimental colon cancer.

Chemoprevention directed towards the control of colon carcinogenesis in its early stages should ultimately provide a higher quality of life for people than waiting to treat end-stage disease. Silibinin is a major bioactive compound that is present in the widely consumed dietary supplement Silymarin. The current investigation aimed to explore the effect of the phytochemical silibinin on the suppression of 1,2-dimethylhydrazine-induced colonic preneoplastic changes in a long-term preclinical model. Wistar male rats were divided into six groups: group 1 were control rats, group 2 were control rats that received silibinin alone (50 mg/kg body weight orally everyday), rats in group 3 were injected once weekly with 1,2-dimethylhydrazine (20 mg/kg body weight, subcutaneously 15 times), in addition, group 4 (initiation), group 5 (post initiation) and group 6 (entire period) received silibinin as in group 2. At the end of 32 weeks, the activities of the colonic and faecal biotransforming microbial enzymes were analysed. Modulatory effects were also evaluated using aberrant crypt foci (ACF), dysplastic ACF and tumour incidence as endpoint markers. Silibinin markedly reduced tumour incidence, as compared with the rats treated with unsupplemented 1,2-dimethylhydrazine. The most pronounced inhibition of ACF and dysplastic ACF development was observed in the rats fed with silibinin for the entire period and also during the post initiation period. Silibinin administration also significantly (P<0.05) modulated the biotransforming activity of microbial enzymes. The results of our study suggest that silibinin suppresses 1,2-dimethylhydrazine-induced colon carcinogenesis at various stages and exerts a potential chemopreventive action against colon cancer.

Inhibitory effect of bread crust antioxidant pronyl-lysine on two different categories of colonic premalignant lesions induced by 1,2-dimethylhydrazine.

Colorectal malignancies continue to be one of the most frequent and life-threatening diseases throughout the world. Pronyl-lysine, a product obtained from bread crust, is a potent free radical scavenging antioxidant exerting chemopreventive activity by reducing oxidative stress. This study was conducted to investigate the effects of pronyl-lysine supplementation on the formation of colonic precancerous lesions, circulatory lipid peroxidation, and enzymic antioxidant status in 1,2-dimethylhydrazine-induced colon carcinogenesis. Male Wistar rats were randomized into seven groups; group 1 was control rats, group 2 received pronyl-lysine (2 mg/kg body weight orally) everyday, rats in groups 3-7 were administered subcutaneous 1,2-dimethylhydrazine (20 mg/kg body weight) once a week for 15 consecutive weeks. In addition, group 4 (pre-initiation), 5 (initiation), 6 (post-initiation), and 7 (entire period) received pronyl-lysine (2 mg/kg body weight orally) everyday. At the end of 34 weeks, indicative markers of lipid peroxidation and changes in antioxidant defense system were measured in circulation. The results showed that 1,2-dimethylhydrazine significantly increased total aberrant crypt foci formation, total number of dysplastic foci, beta-catenin accumulated crypts and proliferating cell nuclear antigen labeling index in the colon, and enhanced lipid peroxidation markers and decreased enzymic antioxidant activities in the plasma and erythrocyte lysate as compared with untreated controls. Pronyl-lysine supplementation significantly reversed the changes as compared with the rats treated with 1,2-dimethylhydrazine alone. The effect of pronyl-lysine was more pronounced when supplemented throughout the study period (group 7). These findings suggest that pronyl-lysine suppresses 1,2-dimethylhydrazine-induced colon carcinogenesis effectively.

Chemopreventive efficacy of pronyl-lysine on lipid peroxidation and antioxidant status in rat colon carcinogenesis.

Colon cancer is a serious health problem in most of the countries and is the leading cause of cancer mortality throughout the world. The major objective of this study was to examine the chemopreventive effect of dietary pronyl-lysine (2 mg/kg body weight), a bread crust antioxidant, on intestinal and colonic tissue lipid peroxidation (LPO) and antioxidant status in rat colon carcinogenesis. Male Wistar rats were divided into seven groups and were fed a modified pellet diet for 34 weeks. Rats were given a weekly subcutaneous injection of 1,2-dimethyl hydrazine (DMH) (20 mg/kg body weight) for the first 15 weeks. Pronyl-lysine was supplemented to rats during the pre-initiation, initiation, post-initiation and also throughout the study period. All the rats were sacrificed at the end of 34 weeks and their colons were evaluated histologically. The activity of lipid peroxidation (LPO) and antioxidant status in the tissues such as the intestines, colon and cecum were estimated. Our results showed diminished levels of colonic, and cecal LPO products such as conjugated dienes, lipid hydroperoxides and thiobarbituric acid reactive substances, and also reduced activities of the antioxidants superoxide dismutase, catalase and glutathione dependent enzymes (glutathione peroxidase, glutathione-S-transferase, glutathione reductase) in DMH-treated rats, while on supplementing dietary pronyl-lysine the levels of LPO products and antioxidants were significantly reversed (P < 0.05). Thus, our results strongly suggest that the administration of pronyl-lysine throughout the study period (group 7) and the post-initiation (group 6) stages of colon carcinogenesis significantly inhibits colon cancer incidence and prevents DMH induced histopathological lesions.

Resveratrol attenuates 1,2-dimethylhydrazine (DMH) induced glycoconjugate abnormalities during various stages of colon carcinogenesis.

Although a myriad of health promoting effects has been attributed to resveratrol (Res) (3,5,4'-trihydroxy-trans-stilbene), a phytoalexin, the most interesting is its anticancer property. The aim of this work was to elucidate the effectiveness of Res against cellular transformation (glycoconjugate alterations) initiated by 1,2-dimethylhydrazine (DMH), a colon specific carcinogen. Group 1 were control rats, group 2 were control rats that received Res (8 mg/kg body weight orally every day), rats in groups 3-6 were treated weekly with DMH (20 mg/kg body weight, subcutaneously x 15 times). In addition, groups 4-6 received Res (as in group 2) in three dietary regimens: initiation (I), post-initiation (PI) and entire period (EP). At the end of the 30 week experimental period in DMH alone exposed rats, altered levels of glycoconjugates (total hexoses, fucose, hexosamine and sialic acid) were observed in liver, intestine and colon tissues. Of the three dietary regimens of Res, the entire period supplementation significantly (p < 0.01) modulated the levels of glycoconjugates and reduced the incidence of adenoma and adenocarcinoma. These findings suggest that Res may extend its chemopreventive effect by restoring the alteration in glycoconjugates that are thought to be involved in the colonic malignant transformation process in this experimental model.

Hesperetin exerts dose dependent chemopreventive effect against 1,2-dimethyl hydrazine induced rat colon carcinogenesis.

Colon cancer is still one of the leading causes of death in USA and is increasing at an alarming rate in Asia. It is one of the major causes of death in industrialized countries, and its etiology is known to be a combination of hereditary, environmental, dietary factors and lack of physical activity. Chemoprevention plays a potential role in colorectal cancer. The present study was performed to evaluate the efficacy of hesperetin supplementation on colonic aberrant crypt foci, lipid peroxidation and antioxidant defense system in 1,2-dimethylhydrazine (DMH) induced colon carcinogenesis in male Wistar rats. The rats were segregated into six groups viz., group 1, control rats received modified pellet diet; group 2 rats received modified pellet diet along with hesperetin (30 mg/kg body weight/day); groups 3-6 administrated DMH (20 mg/kg body weight) subcutaneous injection once a week for the first 4 weeks; in addition groups 4-6 received hesperetin at three different doses of 10, 20 and 30 mg/kg body weight/day for 16 weeks. All the rats were sacrificed at the end of the experimental period of 16 weeks. Increased tumor incidence and increased number aberrant crypt foci (ACF) accompanied by a decrease in the tissue lipid peroxidation, glutathione S-transferase (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) activities were observed in DMH-treated rats. Administration of hesperetin to DMH treated rats significantly decreased the tumor incidence, the number of aberrant crypt foci with simultaneous enhancement of tissue lipid peroxidation, GST, GPx, SOD, and CAT activities. The results of this study suggest that hesperetin at a dose of 20 mg/kg body weight showed a significant beneficial effect against chemically induced colonic carcinogenesis in rats as compared to the other two doses.