Suppressive effect of 1,4-phenylene diisothiocyanate onN-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in male ICR mice

Abstract

The modifying effects of dietary administration of 1,4-phenylene diisothiocyanate (DITC) on N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced urinary bladder carcinogenesis during the initiation and post-initiation phases were examined in male ICR mice. Five-week-old animals were divided into 5 groups. Groups 1-3 were given BBN (500 ppm) in drinking water for 6 weeks starting at age 6 week. Mice in Group 2 were given the diet containing 100 ppm DITC for 8 weeks during the initiation phase, starting 1 week before BBN exposure. Animals in Group 3 were fed the experimental diet for 24 weeks during the post-initiation phase starting 1 week after the cessation of BBN exposure. Mice in Group 4 were given only the diet containing the test compound, and those in Group 5 were given the basal diet alone throughout the experiment (32 weeks). The frequency of bladder lesions, neoplasms, dysplasia and hyperplasia, was analyzed histopathologically. The cell-proliferation activity estimated by the 5-bromodeoxyuridine labeling index (BrdU-LI), and cell cycle progression by counting cyclin D1-positive cell ratios were compared among the groups using immunohistochemistry. Administration of DITC in the initiation phase reduced significantly the incidence of urinary bladder carcinoma and dysplasia. The frequencies of any lesions of urinary bladder were not reduced by DITC in post-initiation phase. Dietary exposure of this agent in initiation phase reduced significantly both BrdU-LI and cyclin D1-positive cell ratios in any bladder lesions. Administration of DITC in post-initiation phase also significantly reduced BrdU-LI in bladder neoplasms and hyperplasia and cyclin D1-positive cell ratios in urinary bladder carcinoma as well as dysplasia. These results suggest that dietary DITC could be a preventive agent against BBNinduced bladder carcinogenesis in mice when fed during the initiation phase. ' 2005 Wiley-Liss, Inc.Key words: chemoprevention; DITC; BBN; cyclin D1; BrdU labeling index; urinary bladder carcinogenesis Epidemiologic studies suggest that the consumption of green and yellow vegetables has an inverse relationship with cancer risk. [1][2][3][4][5][6][7] Organosulfur compounds that are present abundantly in a group of cruciferous vegetables or allium species have been shown to possess cancer chemopreventive properties. [8][9][10] Especially, isothiocyanates (ITC) are versatile chemopreventive agents in many animal systems.Cancer prevention studies of our group have demonstrated that benzyl isothiocyanate (BITC) inhibit methylazoxymethanol (MAM)-acetate induced intestinal carcinogenesis and diethylnitrosamine (DEN) induced hepatocarcinogenesis in rats, and sinigrin reduced 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis and DEN-induced hepatocarcinogenesis.11-14 We also found that BITC reduced not only unscheduled DNA synthesis (UDS) but also replicative DNA synthesis (RDS), induced by some genotoxic carcinogens, e.g., 2-acetylaminofluorene (AAF), MAM acetate, 9,10-dimethyl-1,2-benzanthracene (DMBA), and DEN....

Peroxisome proliferator activated receptor in colonic epithelial cells protects against experimental inflammatory bowel disease

“…[9][10][11][12] Genetic studies in mouse models have revealed a role for this receptor in the control of blood pressure 13 and renal fluid retention 14 15 in the kidney. PPARc was found to have tumour suppressor effects in the colon and other tissues [16][17][18][19][20][21] although controversy still exists regarding its role in the colon in mouse models of carcinogenesis. 22 In humans, an allelic variant of PPARc that exhibits increased sensitivity to ligand activation and is associated with a reduced risk of type II diabetes 23 appears to protect against colon adenomas.…”

Dietary β-cryptoxanthin inhibits N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in male ICR mice

“…We previously reported that ceratin cancer chemopreventive agents reduced the incidence and multiplicity of epithelial malignancy in the target tissues by lowering the cyclin D1-positive ratio (16,25,26,28,29,38,39). A significant relationship between cyclin D1 over-expression and tumor grade or stage was also reported in human transitional cell carcinomas (32).…”

“…In the current study, ß-cryptoxanthin effectively suppressed cyclin D1-positive cell ratios of various urinary bladder lesions, implying that reduction in the incidence of tumors and preneoplastic lesions of urinary bladder is related to effectively suppressed cell cycle progression by the treatment with ß-cryptoxanthin. In a previous study, selective cyclin D1 inhibitors, silymarin (25) and 1,4-phenylene diisothiocyanate (26), possessed chemopreventive potential on BBN-induced urinary bladder carcinogenesis in male ICR mice.…”

“…In the current study, chemopreventive effects of ß-cryptoxanthin were evaluated by dietary exposure during the postinitiation stage of N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN)-induced urinary bladder carcinogenesis in male ICR mice. This animal model can be applied to detect the modifying effects of natural or synthetic xenobiotics, as we reported (10,(23)(24)(25)(26). Effects of dietary ß-cryptoxanthin on cell cycle progression (cyclin D1) in the bladder epithelium of mice exposed to OH-BBN were also evaluated by immunohistochemical analysis, since alteration of cell cycle progression may be involved in cancer chemoprevention (25)(26)(27)(28)(29).…”

Pathobiology and Chemoprevention of Bladder Cancer

“…They include astaxanthin [224], protocatechuic acid [225], diosmin [226], hesperidin [226], silymarin [227], 1,4-phenylene diisothiocyanate [228], and β -cryptoxanthin [229]. These compounds are ready to be evaluated for efficacy in clinical trials.…”