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.

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.

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.

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.

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.

Effect of hesperetin, a citrus flavonoid, on bacterial enzymes and carcinogen-induced aberrant crypt foci in colon cancer rats: a dose-dependent study.

Hesperetin, an important bioactive compound in Chinese traditional medicine, has antioxidant and anticarcinogenic properties. Hesperetin is found in abundance in orange and grape juices (200-590 mg L(-1)) consumed in the daily diet. We have investigated the effect of different doses of hesperetin on faecal and colonic mucosal bacterial enzymes and aberrant crypt foci (ACF) in 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in male Wistar rats. The rats were divided into six groups and were fed a modified pellet diet for 16 weeks. Group 1 served as control and group 2 received the modified pellet diet along with hesperetin (30 mg kg(-1)). The rats in groups 3-6 rats were given a weekly subcutaneous injection of DMH (20 mg kg(-1)) for the first four weeks. Hesperetin was supplemented orally at different doses (10, 20 or 30 mg kg(-1)) for a total of 16 weeks. At the end of the experimental period all rats were killed. In DMH-treated rats, the activity of faecal and colonic mucosal bacterial enzymes, such as beta-glucuronidase, beta-galactosidase, beta-glucosidase, nitroreductase, sulfatase and mucinase, were significantly elevated, but in rats supplemented hesperetin along with DMH the activity was significantly lowered (P < 0.05). The total number of aberrant crypts was significantly increased in unsupplemented DMH-treated rats, while hesperetin supplementation to DMH-treated rats significantly reduced the total number of crypts. The results demonstrated that hesperetin supplementation at a dose of 20 mg kg(-1) played a potent role in suppressing the formation of aberrant crypt foci and reducing the activity of bacterial enzymes in colon cancer.

Aberrant crypt foci and AgNORs as putative biomarkers to evaluate the chemopreventive efficacy of pronyl-lysine in rat colon carcinogenesis.

Chemoprevention opens new perspectives in the prevention of cancer and other degenerative diseases. Use of target-organ biological models at the histological and genetic levels can markedly facilitate the identification of potential chemopreventive agents. Our aim was to study the chemopreventive efficacy of pronyl-lysine, a key antioxidant present in bread crust by evaluating, the total number of aberrant crypt foci (ACF), their distributions, dysplastic ACF, colonic tumor incidence and the expression of cell proliferation biomarker such as the argyrophilic nucleolar organizing region-associated proteins (AgNORs) in 1,2-dimethylhydrazine (DMH) induced colon cancer in rats. Male Wistar rats were randomized into seven groups, group 1 were control rats, group 2 received pronyl-lysine (2 mg/kg body weight p.o. everyday), rats in groups 3-7 were administered DMH (20 mg/kg body weight) in the groin for 15 weeks. In addition, group 4 (pre-initiation), 5 (initiation), 6 (post-initiation), and 7 (entire period) received pronyl-lysine (2 mg/kg body weight p.o) everyday. At the end of 34 weeks, pronyl-lysine supplementation showed markedly reduced tumor incidence, ACF development and also lowered number of AgNORs. Overall, these findings confirm that pronyl-lysine has a positive beneficial effect against chemically induced colonic preneoplastic progression in rats.

A case control study of glycoprotein status in ovarian carcinoma.

OBJECTIVES: Ovarian cancer is the leading cause of death due to gynecological malignancies. The aim of our study was to investigate the status of circulating glycoprotein levels in ovarian cancer patients. DESIGN AND METHODS: Thirty ovarian cancer patients and an equal number of age-matched, apparently healthy subjects as controls were involved in the study. Glycoprotein levels, as indicated by the concentration of plasma total sialic acid, protein-bound hexoses, hexosamine and fucose were estimated in circulation of both the ovarian cancer patients and controls. RESULTS: Significantly elevated levels of plasma total sialic acid, protein-bound hexoses, hexosamine and fucose were observed in ovarian cancer patients as compared to the apparently healthy controls. CONCLUSION: Plasma total sialic acid, protein-bound hexoses, hexosamine and fucose in the circulation of ovarian cancer patients are markedly elevated and the increase in these carbohydrate moieties of glycoproteins reflect the stage of cancer and may be an additional tool in the diagnosis and prognosis of ovarian carcinoma.

Evidence of oxidative stress in the circulation of ovarian cancer patients.

BACKGROUND: Ovarian cancer is the leading cause of death due to gynecological malignancies among women. The extent of free radical induced oxidative stress can be exacerbated by the decreased efficiency of antioxidant mechanisms. The present study was conducted to investigate the extent of oxidative stress and the levels of antioxidants in the circulation of ovarian cancer patients. METHODS: Plasma thiobarbituric acid reactive substances (TBARS) and conjugated dienes (CD) and the levels of antioxidants such as superoxide dismutase (SOD), catalase (CAT), vitamin C and vitamin E were estimated in the circulation of 30 ovarian cancer patients and an equal number of age-matched normal subjects as control. RESULTS: Significantly increased concentrations of plasma TBARS and CD and significantly lowered levels of SOD, CAT, vitamin C and vitamin E were observed in ovarian cancer patients as compared with normal subjects. CONCLUSION: The low levels of SOD, CAT, vitamin C and vitamin E in the plasma of ovarian cancer patients may be due to their increased utilization to scavenge lipid peroxides as well as their sequestration by tumor cells. Increased levels of lipid peroxidation may be due to excessive oxidative stress caused by incessant ovulation or epithelial inflammation.