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PubMed1995

Modifying effects of naturally occurring products on the development of colonic aberrant crypt foci induced by azoxymethane in F344 rats.

Modifying effects of dietary exposure of seven naturally occurring products on the development of colonic aberrant crypt foci (ACF) induced by azoxymethane (AOM) were investigated in male F344 rats. The effects of these compounds on proliferation biomarkers such as the number of silver-stained nucleolar organizer region protein, ornithine decarboxylase activity, and polyamine concentration in the colon were also estimated. The naturally occurring products tested included four terpenoids (rebaudioside A, oleanolic acid, costunolide, and soyasaponin A2), one flavonoid (liquiritin), and two isocoumarins (phyllodulcin and hydrangenol). Animals were given 3 weekly s.c. injections of AOM (15 mg/kg body weight) to induce ACF. These rats were fed the diet containing 200 ppm of each test chemical for 5 weeks, starting 1 week before the first dosing of AOM. All rats were sacrificed 2 weeks after the last AOM injection to estimate their modulatory effects on the occurrence of ACF and the cell proliferation biomarkers in the colon. In groups of rats given AOM and hydrangenol, oleanolic acid, or costunolide, the frequencies of ACF/colon were significantly lower than that of AOM alone (P < 0.05, P < 0.005, and P < 0.05, respectively). In groups of rats given AOM and costunolide and those treated with AOM and soyasaponin A2, both ornithine decarboxylase activity and polyamine concentration of the colonic mucosal tissue were significantly decreased compared with those in rats given AOM alone (P < 0.05 and P < 0.001 for costunolide and P < 0.001 and P < 0.05 for soyasaponin A2, respectively). In groups of rats given AOM and liquiritin, oleanolic acid, or costunolide, the numbers of silver-stained nucleolar organizer regions/nucleus were significantly lower than that of AOM alone (P < 0.05, P < 0.01, and P < 0.05, respectively). Costunolide decreased four AOM-induced biomarkers, such as the frequencies of ACF/colon, ornithine decarboxylase activity, polyamine concentration level, and silver-stained nucleolar organizer region number in the colon. These results indicate that, among the test chemicals, costunolide has blocking effects against rat colon carcinogenesis and is a possible chemopreventive agent against colon tumorigenesis. Also, the short-term model described here could be a very useful prescreening tool for chemopreventive agents against colon cancer.

Animals↗
PubMed1994

Chemoprevention of azoxymethane-induced colonic carcinogenesis by supplemental dietary ursodeoxycholic acid.

The present studies were conducted at the Universities of Chicago and Arizona to examine and compare the effects of supplemental dietary ursodeoxycholic acid to cholic acid, a known tumor promoter, and to piroxicam, a known chemopreventive agent, in the azoxymethane (AOM) model of experimental colonic carcinogenesis. Male Fischer 344 rats were utilized in these experiments. All animals were fed a basal diet (AIN-76) supplemented with 0.2% or 0.4% cholic acid, 0.2% or 0.4% ursodeoxycholic acid, 0.2% ursodeoxycholic acid plus 0.2% cholic acid, or 75 ppm piroxicam. Rats were given s.c. injections once a week for 2 weeks with AOM (15 mg/kg body wt/week) or vehicle (saline) after being fed their respective diets for 2 weeks. The rats in each group were then maintained on their respective diets for approximately 28 weeks; after sacrifice, their colons were removed and examined macroscopically and microscopically for the presence of tumors. The results of these studies demonstrated that none of the control rats fed the various diets injected with AOM-vehicle developed tumors. In groups receiving AOM, the addition of cholic acid (0.4%) caused a significant increase in the incidence of tumors. In contrast, the addition of 0.2% ursodeoxycholic acid did not promote AOM-induced colonic tumors, and when it was added to a promoting dose of cholic acid (0.2%), 0.2% ursodeoxycholic acid prevented enhancement of tumor promotion. At higher doses (0.4%), supplemental dietary ursodeoxycholic acid significantly reduced the incidence of colon tumors and cancers. Moreover, the tumor suppressive effects of 0.4% ursodeoxycholic acid exceeded that of dietary piroxicam. Our results further emphasize the important role of bile salts in modulating colonic tumor development. These studies also demonstrate for the first time that supplemental dietary ursodeoxycholic acid is a chemopreventive agent in the AOM model of experimental colonic carcinogenesis.

Animals↗
PubMed1993

Inhibitory effect of caffeic acid esters on azoxymethane-induced biochemical changes and aberrant crypt foci formation in rat colon.

Previous work from this laboratory established that caffeic acid esters, present in the propolis of honey bee hives, are potent inhibitors of human colon tumor cell growth, suggesting that these compounds may possess antitumor activity against colon carcinogenesis. The present study was designed to investigate (a) the inhibitory effects of methyl caffeate (MC) and phenylethyl caffeate (PEC) on azoxymethane (AOM)-induced ornithine decarboxylase (ODC), tyrosine protein kinase (TPK), and arachidonic acid metabolism in liver and colonic mucosa of male F344 rats, (b) the effects of caffeic acid, MC, PEC, phenylethyl-3-methylcaffeate (PEMC), and phenylethyl dimethylcaffeate (PEDMC) on in vitro arachidonic acid metabolism in liver and colonic mucosa, and (c) the effects of PEC, PEMC, and PEDMC on AOM-induced aberrant crypt foci (ACF) formation in the colon of F344 rats. At 5 weeks of age, groups of animals were fed diets containing 600 ppm MC or PEC (biochemical study) or 500 ppm PEC, PEMC, or PEDMC (ACF study). Two weeks later, all animals except the vehicle-treated groups were given s.c. injections of AOM, once weekly for 2 weeks. The animals intended for the biochemical study were sacrificed 5 days later and colonic mucosa and liver were analyzed for ODC, TPK, lipoxygenase, and cyclooxygenase metabolites. The animals intended for the ACF study were sacrificed 9 weeks later and analyzed for ACF in the colon. The results indicate that the PEC diet significantly inhibited AOM-induced ODC (P < 0.05) and TPK (P < 0.001) activities in liver and colon. The PEC diet significantly (P < 0.001) suppressed the AOM-induced lipoxygenase metabolites 8(S)- and 12(S)-hydroxyeicosatetraenoic acid (HETE). The animals fed the MC diet exhibited a moderate inhibitory effect on ODC and 5(S)-, 8(S)-, 12(S)-, and 15(S)-HETEs and a significant (P < 0.001) effect on colonic TPK activity. However, the MC and PEC diets showed no significant inhibitory effects on cyclooxygenase metabolism. In an in vitro study, caffeic acid and MC showed inhibitory effects on HETE formation only at a 100 microM concentration, whereas PEC, PEMC, and PEDMC suppressed in vitro HETE formation in a dose-dependent manner. AOM-induced colonic ACF were significantly inhibited in the animals fed PEC (55%), PEMC (82%), or PEDMC (81%). The results of the present study indicate that PEC, PEMC, and PEDMC, present in honey, inhibit AOM-induced colonic preneoplastic lesions, ODC, TPK, and lipoxygenase activity, which are relevant to colon carcinogenesis.

Animals↗
PubMedDate not supplied

Fasting/refeeding enhances the crypt multiplicity in rat colon carcinogenesis induced by azoxymethane.

Aberrant crypt foci (ACF) are putative preneoplastic lesions of colon cancer which are being utilized currently as a biological end point to evaluate the induction and modulation of colon carcinogenesis. In rodents, caloric restriction reduces carcinogen-induced colon cancer incidence. The present study was designed to investigate the effect of fasting followed by refeeding on the development of ACF. Male Fisher 344 rats were fasted for 4 days and they were given a single injection of azoxymethane (AOM) at the dose of 20 mg/kg body weight on the first day of refeeding, and killed 3 months later. Controls were fed ad libitum and received the same dose of AOM. The number and crypt multiplicity (number of crypts/focus) of ACF were measured on the medial colon. No effect of fasting/refeeding was observed in the total number of foci/medial colon. On the contrary, rats fasted for 4 days and refed developed foci with higher number of crypts than fed controls. Our results are of particular interest because the crypt multiplicity, rather than the number of foci, is a consistent predictor of tumor incidence. As a consequence these data suggest a possible role of fasting/refeeding in enhancing the colon tumor outcome.

Animals↗
PubMed1998

Effects of feeding fresh garlic and garlic oil on detoxifying enzymes and micronuclei formation in rats treated with azoxymethane.

The effect of feeding a fresh garlic or garlic oil-supplemented diet was studied in rats for a period of 23 weeks with or without the treatment of a carcinogen azoxymethane (AOM), on the modulation of detoxification enzymes and micronuclei formation. The results showed that feeding fresh garlic or garlic oil-supplemented diets tended to reduce hepatic lipid peroxidation, though not to significant levels. Glutathione content was also not altered. The catalase activity in liver of rats fed a fresh garlic-supplemented diet was reduced compared to that of the control diet; however, the activity was not affected by AOM treatment. Ingestion of garlic caused a 40 percent increase in the hepatic glutathione peroxidase activity, whereas carcinogen treatment reduced it. The activity of hepatic glutathione-S-transferase was unaffected by the feeding regimen, while it was lowered in the garlic oil diet group treated with AOM. The gamma glutamyl transpeptidase activity was elevated more than sevenfold, in the kidney of rats treated with AOM, while it was reduced almost to half when the AOM-treated rats were fed fresh garlic or garlic oil. Micronuclei formation was increased fourfold, in rats exposed to AOM whereas the increase was reduced to half when AOM-injected groups had either fresh garlic or garlic oil in their diet. From these studies, it is concluded that long-term feeding of garlic, fresh or oil, reduced the toxic effect of AOM in rats.

Allyl Compounds↗
PubMed2005

Lack of large intestinal carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine at low doses in rats initiated with azoxymethane.

2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), an abundant food-derived heterocyclic amine (HCA), has attracted particular attention as a human colon carcinogen. Humans are in fact exposed to continuous low doses of HCAs during lifetime. Therefore, we focused on rat large intestinal carcinogenicity of PhIP at levels that mimic practical human exposure. A total of 192 6-week-old male F344 rats were subcutaneously injected twice with 15 mg/kg body weight azoxymethane (AOM), then continuously fed various doses (0, 0.001, 0.01, 0.1, 1, 10, 50 and 200 ppm) of PhIP in the diet. At week 16, aberrant crypt foci (ACF) were quantitatively analyzed. At week 36, tumor occurrence was pathologically analyzed. Then immunohistochemical examinations were performed. PhIP was found to enhance strongly AOM-initiated rat large intestinal tumorigenesis at high doses (50 and 200 ppm), while lower doses (0.001-10 ppm) had no apparent effects. High doses also caused variation in tumor histologic types and their distribution throughout the large intestinal segments. Frequencies of ACF/cm(2) did not meaningfully vary between the groups. Cellular proliferation activity in normal-appearing colonic mucosa was significantly increased at high doses. These novel findings may provide evidence of a low-dose potential for PhIP, with a no-observed effect level speculated to be 10 ppm in the present initiation-promotion experimental model.

Animals↗
PubMed2003

Defective processing of the transforming growth factor-beta1 in azoxymethane-induced mouse colon tumors.

High levels of the cell growth inhibitor transforming growth factor-beta1 (TGF-beta1) are often found in a variety of human cancers. However, the physiological significance of this overexpression depends on the availability of the biologically active form of TGF-beta1 within the extracellular matrix of the tumor microenvironment. To determine the expression and activation status of TGF-beta1 in chemically induced tumors, 6-wk-old A/J mice were injected intraperitoneally with either azoxymethane (AOM) (10 mg/kg body weight, once a week for 6 wk) or normal saline solution, and colon tumors were isolated 24 wk following the last injection. An enzyme-linked immunosorbent assay for TGF-beta1 revealed a significant increase (1.7-fold, P < 0.05) in total TGF-beta1 protein in tumors. Interestingly, while 80% of the total TGF-beta1 in the control colon tissues was in the active form, only 50% was found to be active in tumors. Together with our earlier observations that TGF-beta1 mRNA levels are unchanged in A/J tumors, these data further support a mechanism whereby elevated TGF-beta1 levels result from a defective activation and turnover of this protein. Because plasmin is known to be a major activator of TGF-beta1 in vivo, we hypothesized that reduced plasmin activity may be responsible for the observed dysregulation of TGF-beta1 processing in these behaviorally benign tumors. With a fluorogenic peptide substrate for serine proteases, a deficiency in plasmin activity was found in the tumors. Furthermore, semiquantitative reverse transcription (RT)-polymerase chain reaction (PCR) analysis of a panel of genes involved in the plasminogen activation system, including plasminogen activator inhibitor-1 (PAI-1), urokinase-plasminogen activator (u-PA), and urokinase-receptor (u-PAR-1), demonstrated a significant upregulation (approximately fourfold to sixfold, P < 0.05) in the expression of each of these genes in the tumor tissue. In addition, no significant changes were observed in the expression levels of thrombospondin-1 (TSP-1) and insulin-like growth factor type II receptor (IGF-IIR), which also mediate the activation of latent TGF-beta1. To gain further insight into the functionality of the TGF-beta1 pathway, cDNA microarrays were performed and the expression levels of a panel of 21 TGF-beta1-specific target genes were determined in AOM-induced tumors that overexpress the ligand. A significant dysregulation in the expression of each of these targets was observed, providing evidence of aberrant TGF-beta1 signaling in tumors. Overall, the present study demonstrates a very low plasmin activity in A/J colon tumors, possibly as a result of the potent inhibitory effect of PAI-1 on the plasminogen activation cascade. The observed deficiency in plasmin activity may not be sufficiently compensated for by other mechanisms of latent TGF-beta1 activation, including TSP-1 and IGF-IIR, thereby resulting in a decreased fraction of the biologically active form of TGF-beta1 and subsequent aberration in TGF-beta1-specific gene regulation in A/J tumors.

Animals↗
PubMed2005

Vascular endothelial growth factor and enhanced angiogenesis do not promote metastatic conversion of a newly established azoxymethane-induced colon cancer cell line.

The organo-specific carcinogen, azoxymethane (AOM), produces colon tumors in mice that share many pathological features with sporadic human colorectal cancer (CRC). An important distinction between AOM-induced CRC and human CRC is lack of mucosal invasion in the murine model. To assess the role of the microenvironment in preventing the invasive phenotype, multiple benign in situ adenocarcinomas were harvested from AOM-treated mice and cultured in vitro. However, tumor cell growth was extremely limiting under standard culturing conditions. Thus, we injected tumor cells directly into nude mice and performed two serial transplants, and successfully explanted a rapidly growing epithelial tumor cell line (AJ02nm(0)). When injected subcutaneously (sc) into nude mice, AJ02nm(0) cells formed well-differentiated adenocarcinomas with minimal tumor invasive capacity. To define whether metastatic and invasive potential were related to lack of angiogenic stimuli, the AJ02nm(0) cells were transfected to overexpress murine vascular endothelial growth factor-164 (VEGF(164)). AJ02nm-VEGF cells produced rapidly growing tumors in nude mice that exhibited extensive pseudo-epithelial ductal architecture and supporting vasculature, but without increased invasive potential compared to controls. The established murine colon epithelial cell line provides a useful experimental model to further elaborate genetic and epigenetic factors that may promote or inhibit colon tumorigenesis and metastasis.

Animals↗
PubMed2000

Diallyl sulfide enhances azoxymethane-induced preneoplasia in Fischer 344 rat colon.

Azoxymethane (AOM) is an indirect-acting colon carcinogen that produces a high incidence of precancerous lesions, referred to as aberrant crypt foci (ACF), in rats. This study was undertaken to determine whether high dose gavage administration of the cytochrome P-450 2E1 (CYP2E1) inhibitor and chemopreventive agent, diallyl sulfide, would reduce the incidence and severity of ACF formation in the distal colons of AOM-treated Fischer 344 rats. Seven-week-old male rats received 150 or 50 mg/kg diallyl sulfide by gavage 24 and 2 h prior to two weekly i.p. injections of AOM (20 mg/kg). Ten weeks after the last injection of AOM the rats were sacrificed and the colons removed and stained with 0.2% methylene blue. ACF were visualized using stereomicroscopy. Rats pretreated with diallyl sulfide exhibited a significant increase in the number of ACF/cm in the distal colon compared with rats receiving AOM alone. This increase in ACF number was seen in ACF of all sizes. To examine the effects of diallyl sulfide on the initiation stage of AOM-induced carcinogenesis, mutations in the K-ras proto-oncogene were also investigated. ACF and normal appearing colonic mucosa (0.2-0.5 mm3) were microdissected for subsequent PCR-RFLP analysis of a codon 12 (GGT-GGA) activating mutation in the K-ras gene. Greater than 90% of ACF from AOM-treated animals, regardless of diallyl sulfide treatment, exhibited activating K-ras mutations. K-ras mutations were also detected in normal appearing mucosa of AOM-treated animals, although at a lesser frequency (15-35%). These studies demonstrate that diallyl sulfide given in large gavage doses enhances AOM-induced preneoplasia in rats and suggests that diallyl sulfide may alter the disposition of AOM intermediates and/or enhance colonic promotional activity in the rat.

Allyl Compounds↗
PubMed1997

Effects of dietary bile acids on formation of azoxymethane-induced aberrant crypt foci in F344 rats.

The present study has demonstrated the influence of bile acids (BAs) on the development and growth of azoxymethane (AOM)-induced aberrant crypt foci (ACF). Male F344 rats were treated with two doses of AOM (15 mg/kg) at 7 days apart and fed either basal MF or MF plus 0.4% of cholic (CA), deoxycholic (DCA), chenodeoxycholic (CDCA), lithocholic (LCA) and ursodeoxycholic (UDCA) acid mixed diets for 8 weeks after the first AOM dose. The mean number of ACF/colon of the rats fed CA, DCA, CDCA and LCA were higher than that of MF-fed group and the differences were statistically significant (P < 0.005). But the mean number of ACFs/colon was significantly (P < 0.005) lower in UDCA diet-fed rats compared to MF. UDCA-fed rats also showed a significant decrease in average crypt multiplicity (number of crypts/focus) of ACF compared to MF alone. The mean number of ACF with > or =5 crypts was about 2.5-3.7 times higher in case of CA, DCA, CDCA and LCA and about 8.2 times lower in UDCA compared to the control MF diet group. In a parallel study, feeding for 18 weeks of the same BAs mixed diets without AOM administration did not significantly induce ACF. Therefore, these data suggest that dietary BAs by themselves do not induce ACF in F344 rats but enhance or, in the case of UDCA, suppress the development and growth of AOM-induced ACF.

Animals↗
PubMed1998

Inhibitory effects of plumbagin and juglone on azoxymethane-induced intestinal carcinogenesis in rats.

The effects of two naphthoquinones, juglone and plumbagin, and an isocoumarin, hydrangenol, on intestinal carcinogenesis in rats were examined by dietary exposure during the initiation phase. Starting at 5 weeks of age, male F344 rats were fed the diets containing either of the test chemicals at a concentration of 200 ppm or the control diet without the compounds. At 6 weeks of age, all animals were treated with s.c. injections of azoxymethane (AOM) (15 mg/kg body weight, once weekly for 3 weeks) or saline alone. Animals fed experimental diets were changed to the control diet 1 week after the last carcinogen treatment. Animals given plumbagin together with the carcinogen had a lower incidence (41%) and smaller multiplicity (0.48 +/- 0.62) of tumors in the entire intestine compared with those exposed to carcinogen alone (68% and 1.04 +/- 0.62) (P < 0.05 and < 0.01, respectively). The incidence and multiplicity of tumors in the small intestine (7% and 0.07 +/- 0.25) and the multiplicity of tumors in the entire intestine (0.60 +/- 0.76) of animals treated with juglone and the carcinogen were significantly less than those of animals treated with carcinogen alone (P < 0.05 in each). Hydrangenol tended to decrease the incidence and the multiplicity of tumors in the entire intestine induced by AOM, but the effect was not statistically significant. The present data suggest that the naphthoquinones, juglone and plumbagin, could be promising chemopreventive agents for human intestinal neoplasia.

Animals↗
PubMed1998

Effects of miso and NaCl on the development of colonic aberrant crypt foci induced by azoxymethane in F344 rats.

The present study was designed to investigate the effects of dietary miso and NaCl supplementation on the development of aberrant crypt foci (ACF) induced by azoxymethane (AOM) in male F344 rats. A total of 76 rats, six weeks of age, were divided into seven groups and given weekly subcutaneous injections of AOM (15 mg/kg body wt) for three weeks to induce ACF. The animals were placed on diets one week before the first AOM dosing. Group 1 was fed a normal diet as a control. Groups 2-4 were fed diets containing 5%, 10%, and 20% miso, respectively, and Groups 5 and 6 were fed diets containing 2.2% and 4.4% NaCl, respectively, for five weeks. Group 7 was fed a normal diet without carcinogen exposure. Dietary miso inhibited the development of ACF in a dose-dependent manner (y = -3.9x + 140, r = -0.94). Thus the mean numbers of ACF per colon were significantly lower in Groups 3 and 4 than in Group 1 (p < 0.01), and there were fewer aberrant crypts per colon in Group 4 than in Group 1. NaCl supplementation was associated with fewer ACF, but this was not statistically significant. 5-Bromo-2'-deoxyuridine labeling indexes in the colonic epithelium were significantly lower in Group 3 than in Group 1 (p < 0.05). The present results indicate that dietary miso could act as a chemopreventive agent for colon carcinogenesis.

Animals↗
PubMed2002

Red wine and black tea polyphenols modulate the expression of cycloxygenase-2, inducible nitric oxide synthase and glutathione-related enzymes in azoxymethane-induced f344 rat colon tumors.

Polyphenolic compounds extracted from red wine (WE) and black tea (BT), 50 mg/(kg. d), inhibit the promotion phase of the colon carcinogenesis process induced by azoxymethane (AOM) in rodents. To investigate possible mechanisms of this protective activity, we evaluated by RT-PCR the gene expression of cycloxygenase-2 (COX-2), inducible NO synthase (iNOS), gamma-glutamylcysteine synthetase (gamma-GCS) and two isoforms of glutathione S-transferase (GST), GST-P and GST-M2, in 30 AOM-induced tumors and in the corresponding normal colon mucosa. AOM-induced colon tumors had significantly greater GST-P, GST-M2, COX-2 and iNOS gene expression than the corresponding normal mucosa. However, tumors harvested from rats treated with BT (P < 0.05) and WE (P < 0.01) polyphenols had a lower GST-P mRNA level than tumors from controls. Treatment with WE polyphenols induced a similar inhibitory effect on the colon tumor overexpression of GST-M2 (P < 0.01), COX-2 (P < 0.05) and iNOS (P < 0.05). In the normal mucosa, rats treated with BT polyphenols had greater gamma-GCS expression than controls (P < 0.01). Our results provide evidence that WE and BT polyphenols modulate COX-2, iNOS and glutathione-related gene expression in tumors, suggesting that these compounds have possible chemotherapeutic activity.

Animals↗
PubMed2000

Inhibitory Effects of Dietary Monoglucosyl-rutin on Azoxymethane-induced Colon Carcinogenesis in Rats.

The dietary effect of monoglucosyl-rutin (M-R), a flavonoid, on azoxymethane (AOM)-induced colon carcinogenesis was investigated in two experiments with 5 week old, F344 male rats. In the first experiment (5 weeks study), effects of MR on AOM (15 mg/kg body weight 3 times weekly)-induced formation of aberrant crypt foci (ACF) in five groups were assessed. In this experiment, group 3 given 500 ppm M-R with AOM had a significantly smaller number of ACF containing 4 or more aberrant crypts than group 1 with AOM alone, and groups 2 and 3 given 100 ppm or 500 ppm M-R respectively had significantly lower BrdU labeling indices in the epithelial cells of large bowel than group 1. For the second experiment, rats were divided into 8 groups. Groups 1-5 were given AOM as in the first experiment. Groups 2-5 were fed diets containing 100ppm or 500ppm M-R for 4 weeks in the initiation phase or 36 weeks in the post-initiation phase. Group 6 was given 500ppm M-R throughout the experiment, and group 7 was kept on the basal diet and served as a control. At the termination of the experiment (40 weeks after the start), groups 2-5 had significantly smaller numbers of positive cells with anti-proliferating cell nuclea antigen (PCNA) antibody than group 1. Furthermore, group 5 treated with 500ppm M-R for 36 weeks demonstrated tendencies for decrease in the incidence and multiplicity of colon tumors. These data suggest that M-R has the potential to inhibit AOM-induced colon carcinogenesis.

Journal Article↗
PubMed2005

Indole-3-carbinol inhibits the growth of human colon carcinoma cells but enhances the tumor multiplicity and volume of azoxymethane-induced rat colon carcinogenesis.

Indole-3-carbinol (I3C) is a naturally occurring phytochemical which exerts a broad range of biological activities. The purpose of this study was to examine the effects of I3C on colon carcinogenesis, cell proliferation, cell-cycle progression and apoptosis, and on the levels of expression of several cell-cycle control molecules. We used a long-term rat model by using azoxymethane (AOM) to induce tumors (adenomas and adenocarcinomas) in the colon. In the present study, we found that after AOM injection, the treatment of male F344 rats with 0.01 and 0.05% I3C caused a significant increase in the tumor multiplicity of adenocarcinomas by 2.2- (P<0.05 for 0.01% I3C) and 2.1-fold (P<0.0002 for 0.05% I3C) respectively, when compared to the control rats. In addition, the tumor multiplicity of adenoma plus adenocarcinoma and the volume of adenocarcinoma were also increased by 2.0- (P<0.00001) and 2.1-fold (P<0.05) respectively, compared to the control. I3C significantly increased the proliferating cell nuclear antigen labeling index (PCNA LI) (P<0.008) and decreased the apoptotic index (P<0.05) of the colon adenocarcinoma. In contrast, in HCT 116 and HT29 human colon carcinoma cells, I3C inhibited growth and induced G1-phase cell-cycle arrest and apoptosis. Furthermore, I3C caused approximately a 2- to 4-fold increase in the cellular levels of p27KIP1 and p21CIP1 mRNA. These results suggest that I3C inhibits the growth of human colon carcinoma cells, at least in part, by inducing p27KIP1 and p21CIP1-mediated G1 cell-cycle arrest but dietary I3C promotes AOM-induced rat colon carcinogenesis by inhibiting the apoptosis of colon tumors. Therefore, the present study may provide further evidence for the ambivalent modulatory activity of I3C and this information may be useful when including I3C in cancer chemoprevention and/or extensive clinical therapy trials.

Adenocarcinoma↗
PubMed2002

Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane-induced colon carcinogenesis in male F344 rats.

The modifying effect of dietary administration of the polyphenolic antioxidant flavonoid silymarin, isolated from milk thistle [Silybum marianum (L.) Gaertneri], on AOM-induced colon carcinogenesis was investigated in male F344 rats. In the short-term study, the effects of silymarin on the development of AOM-induced colonic ACF, being putative precursor lesions for colonic adenocarcinoma, were assayed to predict the modifying effects of dietary silymarin on colon tumorigenesis. Also, the activity of detoxifying enzymes (GST and QR) in liver and colonic mucosa was determined in rats gavaged with silymarin. Subsequently, the possible inhibitory effects of dietary feeding of silymarin on AOM-induced colon carcinogenesis were evaluated using a long-term animal experiment. In the short-term study, dietary administration of silymarin (100, 500 and 1,000 ppm in diet), either during or after carcinogen exposure, for 4 weeks caused significant reduction in the frequency of colonic ACF in a dose-dependent manner. Silymarin given by gavage elevated the activity of detoxifying enzymes in both organs. In the long-term experiment, dietary feeding of silymarin (100 and 500 ppm) during the initiation or postinitiation phase of AOM-induced colon carcinogenesis reduced the incidence and multiplicity of colonic adenocarcinoma. The inhibition by feeding with 500 ppm silymarin was significant (p < 0.05 by initiation feeding and p < 0.01 by postinitiation feeding). Also, silymarin administration in the diet lowered the PCNA labeling index and increased the number of apoptotic cells in adenocarcinoma. beta-Glucuronidase activity, PGE(2) level and polyamine content were decreased in colonic mucosa. These results clearly indicate a chemopreventive ability of dietary silymarin against chemically induced colon tumorigenesis and will provide a scientific basis for progression to clinical trials of the chemoprevention of human colon cancer.

Animals↗
PubMed2006

Inhibitory effect of linoleic acid on transformation of IEC6 intestinal cells by in vitro azoxymethane treatment.

The effect of linoleic acid (LA) on growth and transformation of IEC6 intestinal cells was examined. IEC6 cells expressed mRNAs of 15-lipooxygenase (LOX15) and peroxisome proliferator-activated receptor (PPAR)gamma but not COX-2. Cell growth was suppressed by LA in a dose-dependent manner in IEC6 cells. Three-week treatment with LA provided IEC6 cells a quiescent state. LA-induced growth inhibition was abrogated by exposure to antisense S-oligodeoxynucleotides (S-ODNs) for LOX15 and/or PPARgamma. In an in vitro carcinogenesis model, IEC6 cells, which had confirmed CYP2E1 expression and activity, were continuously treated with AOM and/or LA for 40 weeks. DNA injury in AOM-treated cells was suppressed to the control level by concurrent LA treatment. Colony formation of AOM-treated cells in soft agar was suppressed by treatment with LA, which was reversed by exposure to antisense S-ODNs for LOX15 and/or PPARgamma. AOM-treated IEC6 cells formed s.c. tumors in 9 of 12 mice, whereas AOM+LA-treated cells formed no tumor. IEC6 cells showed no remarkable alteration of protein production by AOM treatment, whereas cells treated with AOM+LA showed decreased epidermal growth factor receptor (EGFR) and phospho-EGFR and increased BAX. These findings suggest that LA inhibited AOM-induced transformation of COX-2-negative IEC6 cells, which was possibly mediated with PPARgamma ligands generated by LOX15 from LA.

Animals↗
PubMed2002

Effects of long-term administration of sulindac on APC mRNA and apoptosis in colons of rats treated with azoxymethane.

PURPOSE: Non-steroidal anti-inflammatory drugs, including sulindac, have been shown to exhibit anti-colon cancer activity; however, the detailed mechanisms concerning continuous long-term administration are still unclear. Therefore, we examined the anti-colon carcinogenesis effects of sulindac after prolonged administration. METHODS: Administration of AOM, a colon-specific carcinogen, induced colonic preneoplastic lesions, which can progress to carcinomas about 40-50 weeks after AOM administration. We studied the effects of sulindac on the incidence of preneoplastic lesions, proliferative activity of colonic cells (AgNORs), tumor suppressor adenomatous polyposis coli (APC) gene expression, and apoptosis using AOM-treated rat colon mucosa at 4 weeks and 40 weeks (early and late stage of colon carcinogenesis, respectively). RESULTS: Sulindac suppressed the development of preneoplastic lesions induced by AOM at 4 weeks and 40 weeks by about 50% ( P<0.01); the proliferative activity of colonic cells increased by AOM was suppressed almost completely. Furthermore, APC expression was significantly increased by sulindac at both the early and late stages ( P<0.01). However, apoptosis was clearly increased at the early stage ( P<0.01), but not at the late stage. CONCLUSIONS: APC overexpression induced by sulindac can suppress colon carcinogenesis at both the early and late stages, but apoptosis might work as one of anti-cancer mechanisms at the early stage of colon carcinogenesis.

Adenomatous Polyposis Coli Protein↗