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PubMed1999

Chemoprevention of colonic aberrant crypt foci by an inducible nitric oxide synthase-selective inhibitor.

Inducible nitric oxide synthase (iNOS) is overexpressed in colonic tumors of humans and also in rats treated with a colon carcinogen. iNOS appear to regulate cyclooxygenase-2 (COX-2) expression and production of proinflammatory prostaglandins, which are known to play a key role in colon tumor development. Experiments were designed to study the inhibitory effects of S,S'-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea (PBIT) a selective iNOS-specific inhibitor, measured against formation of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF). Beginning at 5 weeks of age, male F344 rats were fed experimental diets containing 0 or 50 p.p.m. of PBIT, or 2000 p.p.m. of curcumin (non-specific iNOS inhibitor). One week later, rats were injected s.c. with AOM (15 mg/kg body wt, once weekly for 2 weeks). At 17 weeks of age, all rats were killed, colons were evaluated for ACF formation and colonic mucosa was assayed for isoforms of COX and NOS activities. Both COX and iNOS activities in colonic mucosa of the AOM-treated rats were significantly induced. Importantly, 50 p.p.m. PBIT suppressed AOM-induced colonic ACF formation to 58% (P < 0.0001) and crypt multiplicity containing four or more crypts per focus to 78% (P < 0.0001); it also suppressed AOM-induced iNOS activity. Curcumin inhibited colonic ACF formation by 45% (P < 0.001). These observations suggest that iNOS may play a key regulatory role in colon carcinogenesis. Developing iNOS-specific inhibitors may provide a selective and safe chemopreventive strategy for colon cancer treatment.

Animals↗
PubMed1999

Carcinogen and dietary lipid regulate ras expression and localization in rat colon without affecting farnesylation kinetics.

Epidemiological and experimental data suggest that dietary fiber and fat are major determinants of colorectal cancer. However, the mechanisms by which these dietary constituents alter the incidence of colon cancer have not been elucidated. Evidence indicates that dominant gain-of-function mutations short-circuit protooncogenes and contribute to the pathogenesis of cancer. Therefore, we began to dissect the mechanisms whereby dietary fat and fiber, fed during the initiation, promotion and progression stages of colon tumorigenesis, regulate ras p21 localization, expression and mutation frequency. Male Sprague-Dawley rats (140) were provided with corn oil or fish oil and pectin or cellulose plus or minus the carcinogen azoxymethane (AOM) in a 2 x 2 x 2 factorial design and killed after 34 weeks. We have previously shown adenocarcinoma incidence in these animals to be 70.3% (52/74) for corn oil + AOM and 56.1% (37/66) for fish oil + AOM (P < 0.05). Total ras expression as well as ras membrane:cytosol ratio was 4- to 6-fold higher in colon tumors than in mucosa from AOM- or saline-injected rats. Expression of ras in the mucosal membrane fraction was 13% higher for animals fed corn oil compared with fish oil feeding (P < 0.05), which is noteworthy since ras must be localized at the plasma membrane to function. The elevated ras membrane:cytosol ratio in tumors was not due to increased farnesyl protein transferase activity or prenylation state, as nearly all detectable ras was in the prenylated form. Phosphorylated p42 and p44 mitogen activated protein kinase (ERK) expression was two-fold higher in tumor extracts compared with uninvolved mucosa from AOM- and saline-injected rats (P < 0.05). The frequency of K-ras mutations was not significantly different between the various groups, but there was a trend toward a greater incidence of mutations in tumors from corn oil fed rats (85%) compared with fish oil fed rats (58%). Our results indicate that the carcinogen-induced changes in ras expression and membrane localization are associated with the in vivo activation of the ERK pathway. In addition, suppression of tumor development by dietary n-3 polyunsaturated fatty acids may be partly due to a combined effect on colonic ras expression, membrane localization, and mutation frequency.

Alkyl and Aryl Transferases↗
PubMed1999

Chemopreventive effect of S-methylmethane thiosulfonate and sulindac administered together during the promotion/progression stages of colon carcinogenesis.

S-methylmethane thiosulfonate (S-MMTS), isolated from cauliflower and having antiproliferative activity, and the non-steroidal anti-inflammatory drug sulindac have been shown to inhibit chemically induced colon carcinogenesis when they are administered during the initiation and/ or post-initiation stages. The present study was designed to investigate the chemopreventive efficacy of 80 p.p.m. S-MMTS administered during the initiation and post-initiation stages and of S-MMTS and sulindac administered together at low doses (40 and 160 p.p.m., respectively) during the promotion/progression phases (late in the premalignant stage) of colon carcinogenesis. At 5 weeks of age, groups of male F344 rats were fed diets containing 0 (control diet) or 80 p.p.m. S-MMTS. At 7 and 8 weeks of age all rats except those in the vehicle-treated groups were given s.c. injections of 15 mg/kg body wt azoxymethane (AOM). Rats receiving the control diet and intended for the study of inhibition of colon carcinogenesis during the promotion/progression phases were continued on the control diet for 14 weeks after the second AOM treatment; they were then switched to experimental diets containing 80 p.p.m. S-MMTS, 160 p.p.m. sulindac or 40 p.p.m. S-MMTS plus 160 p. p.m. sulindac. The rats were maintained on their respective dietary regimens until 52 weeks after carcinogen treatment and were then killed. Colon tumors were evaluated histopathologically. Administration of 80 p.p.m. S-MMTS alone during the initiation and post-initiation stages and promotion/progression stages had no significant effect on colon tumor inhibition. In contrast, the administration of 160 p.p.m. sulindac during the promotion/progression stages did significantly inhibit total colon tumor multiplicity (P < 0.05). Moreover, co-administration of 40 p.p. m. S-MMTS with 160 p.p.m. sulindac during the promotion/progression stages suppressed the incidence and multiplicity of non-invasive adenocarcinomas (P < 0.05-0.01) and multiplicity of invasive and total adenocarcinomas of the colon to a significant degree (P < 0. 05-0.01). These findings have potential clinical implications.

Adenocarcinoma↗
PubMed2000

Folate deficiency reduces the development of colorectal cancer in rats.

Alterations in folate status may play an important role in carcinogenesis. The aim of this study was to examine the effect of a diminished folate status on azoxymethane (AOM)-induced intestinal tumours in Sprague-Dawley rats. A total of 125 weanling male rats were divided into five equal groups and fed semi-purified diets containing either 8 mg/kg folate or no folate. After 4 weeks on experimental diets, all animals received three weekly subcutaneous injections of AOM at a dose rate of 15 mg/kg bodyweight. The animals were necropsied after 26 weeks. Rats with a diminished folate status, evident by significantly reduced blood and colonic folate concentrations and elevated plasma homocysteine levels, had significantly (P < 0.01) lower incidence and number of small intestinal and colonic tumours compared with rats displaying an adequate folate status. There was a significant decrease in the incidence of colonic adenocarcinomas (P < 0.01) and size of colonic tumours observed in the rats displaying a diminished folate status. This study shows that a diminished folate status was associated with a decrease in the development of AOM-induced colorectal cancers. The decrease in risk may be attributed to the known role of folate in cell multiplication.

Adenocarcinoma↗
PubMed2000

Chemoprevention of colonic aberrant crypt foci in Fischer rats by sulforaphane and phenethyl isothiocyanate.

Epidemiological studies have linked consumption of broccoli to a reduced risk of colon cancer in individuals with the glutathione S-transferase M1 (GSTM1) null genotype. GSTs are involved in excretion and elimination of isothiocyanates (ITCs), which are major constituents of broccoli and other cruciferous vegetables and have cancer chemopreventive potential, so it is speculated that ITCs may play a role in protection against human colon cancer. However, there is a lack of data from animal studies to support this. We carried out a bioassay to examine whether sulforaphane (SFN) and phenethyl isothiocyanate (PEITC), major ITCs in broccoli and watercress, respectively, and their corresponding N:-acetylcysteine (NAC) conjugates, show any chemopreventive activity towards azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in F344 rats. Groups of six male F344 rats were treated with AOM subcutaneously (15 mg/kg body wt) once weekly for 2 weeks. SFN and PEITC and their NAC conjugates were administered by gavage either three times weekly for 8 weeks (5 and 20 micromol, respectively) after AOM dosing (post-initiation stage) or once daily for 3 days (20 and 50 micromol, respectively) before AOM treatment (initiation stage). The bioassay was terminated on week 10 after the second AOM dosing and ACF were quantified. SFN, SFN-NAC, PEITC and PEITC-NAC all significantly reduced the formation of total ACF from 153 to 100-116 (P < 0.01) and multicrypt foci from 52 to 27-38 (more than four crypts/focus; P < 0.05) during the post-initiation treatment. However, only SFN and PEITC were effective during the initiation phase, reducing the total ACF from 153 to 109-115 (P < 0.01) and multicrypt foci from 52 to 35 (more than four crypts/focus; P < 0.05). The NAC conjugates were inactive as anti-initiators against AOM-induced ACF. These findings provide important laboratory evidence for a potential role of SFN and PEITC in the protection against colon cancer.

Animals↗
PubMed2000

Promotion of intestinal carcinogenesis by Streptococcus bovis.

The involvement of Streptococcus bovis, an member of the human gut flora, in colorectal neoplastic diseases is an object of controversy. The aim of this study was to determine the effects of S.bovis and of antigens extracted from the bacterial cell wall on early preneoplastic changes in the intestinal tract. Adult rats received i. p. injections of azoxymethane (15 mg/kg body weight) once per week for 2 weeks. Fifteen days (week 4) after the last injection of the carcinogen, the rats received, by gavage twice per week during 5 weeks, either S.bovis (10(10) bacteria) or wall-extracted antigens (100 microg). One week after the last gavage (week 10), we found that administration of either S.bovis or of antigens from this bacterium promoted the progression of preneoplastic lesions through the increased formation of hyperproliferative aberrant colonic crypts, enhanced the expression of proliferation markers and increased the production of IL-8 in the colonic mucosa. Our study suggests that S.bovis acts as a promoter of early preneoplastic lesions in the colon of rats. The fact that bacterial wall proteins are more potent inducers of neoplastic transformation than the intact bacteria may have important implications in colon cancer prevention.

Adenoma↗
PubMed2001

Wheat germ extract inhibits experimental colon carcinogenesis in F-344 rats.

It has been demonstrated for the first time that a wheat germ extract prevents colonic cancer in laboratory animals. Four-week-old inbred male F-344 rats were used in the study. Colon carcinogenesis has been induced by azoxymethane (AOM). Ten rats served as untreated controls (group 1). For the treatment of the animals in group 2, AOM was dissolved in physiologic saline and the animals were given three subcutaneous injections 1 week apart, 15 mg/kg body weight (b/w) each. In two additional groups Avemar (MSC), a fermented wheat germ extract standardized to 2,6-dimethoxy-p-benzoquinone was administered as a tentative chemo-preventive agent. MSC was dissolved in water and was given by gavage at a dose of 3 g/kg b/w once a day. In group 3, animals started to receive MSC 2 weeks prior to the first injection of AOM daily and continuously thereafter until they were killed 32 weeks later. In group 4 the basal diet and MSC were administered only. At the end of the experiment all the rats were killed by exsanguination, the abdominal large vessels were cut under a light ether anesthesia and a complete autopsy was performed. Percentage of animals developing colon tumors and number of tumors per animals: group 1 - 0 and 0; group 2- 83.0 and 2.3; group 3 - 44.8 (P < 0.001) and 1.3 (P < 0.004), group 4 - 0 and 0. All the tumors were of neoplastic nature also histologically. The numbers of the aberrant crypt foci (ACF) per area (cm(2)) in group 2 were 4.85 while in group 3 the ACF numbers were 2.03 only (P < 0.0001).

Animals↗
PubMed2002

Development of a multi-organ rat model for evaluating chemopreventive agents: efficacy of indole-3-carbinol.

Indole-3-carbinol (I-3-C) is among the most widely and popularly known antiestrogens. Due to its putative chemopreventive action, I-3-C is being marketed to the general public in health food establishments. Although it has been demonstrated to prevent cancer in animal bioassays, I-3-C also acts as a promoter in the liver and colon. Because of this potential dual biological activity, it is important to investigate both the inhibitory and promotional activities of I-3-C in multi-organ tumorigenesis animal models. 7,12-Dimethylbenz[a]anthracene, aflatoxin B1 and azoxymethane were used to initiate mammary, liver and colon carcinogenesis, respectively in female Sprague-Dawley rats. The rats were fed continuously on a diet containing I-3-C for 25 weeks after initiation. I-3-C treatment was begun one week after the last carcinogen treatment had been administered. I-3-C treatment resulted in a delay in latency of mammary tumor formation, but did not alter tumor incidence or multiplicity among survivors. In the colon, the protocol produced a 40% decrease in aberrant colon crypt foci. However, in the liver, it strongly-induced GST-P foci in carcinogen-treated (a four-fold increase in volume percent foci) and in the vehicle controls (a 69-fold increase). These data support previous findings in other rodent and fish tumor models that I-3-C both inhibits and promotes carcinogenesis. The results of this study clearly demonstrate that I-3-C is not an appropriate chemoprotective agent for human use, in spite of its effects in the breast and colon in this rat animal model.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2002

Enhanced growth of colorectal aberrant crypt foci in fasted/refed rats involves changes in TGFbeta1 and p21CIP expressions.

We previously demonstrated that fasting/refeeding enhances the initiation phase of liver and colorectal carcinogenesis in rats. The present study was undertaken to establish whether cycles of fasting/refeeding carried out during the promotion phase of carcinogenesis may also affect the formation of aberrant crypt foci (ACF), preneoplastic lesions induced in the colon by azoxymethane (AOM). We were also interested in studying whether this effect might be mediated by changes in the proliferation, apoptosis or expression of TGFbeta1 and p21CIP genes in the colon. 44 male Fisher 344 rats were given a single dose of AOM (20 mg/kg s.c.) and one week later, they were exposed to 5 cycles of 4 days fasting followed by 7-10 days of refeeding (refed rats); controls were regularly fed; the rats were killed 2, 8 or 30 days after the last cycle of fasting. Fasting/refeeding caused a dramatic increase in crypt multiplicity when compared with regularly fed rats (AC/ACF was 4.30 +/- 1.3 in refed and 2.38 +/- 0.4 in regularly fed rats, P < 0.005 means +/- SD), while no significant changes were observed in the number of ACF/colon. In the two experimental groups, cell proliferation was higher in ACF than in the surrounding mucosa, but proliferative indexes were higher and the apoptotic index lower in ACF of refed rats compared with regularly fed rats. TGFbeta1 expression was higher in the ACF of refed rats than in those of fully fed controls while p21CIP was less expressed in refed rats than in controls. These results suggest that fasting/refeeding is a risk factor for colon cancer and must be taken into account for cancer prevention in humans.

Animals↗
PubMed2002

The colonic response to genotoxic carcinogens in the rat: regulation by dietary fibre.

The apoptotic response to DNA damage appears to be an innate biological mechanism for protection against tumourigenesis. It is possible that agents that protect against colorectal cancer act by enhancing the apoptotic deletion of cells suffering DNA damage, with consequent removal of those with tumourigenic mutations. We examined the acute apoptotic response to genotoxic carcinogens ("AARGC") in colonic epithelium and the possibility that dietary fibres of different fermentability might regulate AARGC. To fully define the time-course and nature of AARGC in response to the carcinogen azoxymethane (AOM), a single injection of AOM (10 mg/kg) was given to rats and apoptosis monitored in the colon by light microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling staining over a 72 h period. Having defined the site and time of maximum response, two groups of eight rats were fed diets containing 10% wheat bran fibre (WB; fermentable) or 10% methylcellulose (MC; poorly fermentable) for 4 weeks. Colonic AARGC was compared by light microscopy; lumenal short chain fatty acids (SCFAs) and pH were measured as indicators of the fermentative environment. AOM-induced AARGC was maximal at 8 h and greater in distal compared with proximal colon. Apoptotic cells were situated predominantly in the lower half of the crypt, with the median at position 9 indicating involvement of daughter as well as stem cells. There was no "second wave" of apoptosis within 72 h as follows irradiation in small intestine. Distal colonic AARGC in rats fed WB was twice that in rats fed MC (P < 0.01). Compared with MC, WB significantly lowered lumenal pH and increased all SCFAs including butyrate, while proliferation did not differ between the fibres. Certainly, dietary fibres can regulate AARGC and further studies are warranted to determine if this biological effect is the way in which dietary factors regulate tumourigenesis. Lumenal generation of butyrate may enhance AARGC as butyrate is proapoptotic in vitro.

Animals↗
PubMed2002

Inhibitory effects of mofezolac, a cyclooxygenase-1 selective inhibitor, on intestinal carcinogenesis.

Cyclooxygenase (COX)-2, one enzyme isoform responsible for producing prostanoids from arachidonic acid, contributes to colon carcinogenesis. Recently, genetic disruption of COX-1, the other isoform, was shown to decrease the number of intestinal polyps and prostaglandin E(2) levels in intestinal mucosa, like the case with COX-2 gene disruption, in Min mice. We therefore investigated whether a COX-1 selective inhibitor, mofezolac, suppresses intestinal carcinogenesis in rodents. F344 male rats, receiving azoxymethane (AOM, 15 mg/kg body wt) s.c. injections at 5 and 6 weeks of age, were fed a diet containing 600 or 1200 p.p.m. mofezolac for 4 weeks. The number of aberrant crypt foci (ACFs) per rat and the bromodeoxyuridine labeling index of the crypt epithelium were dose-dependently decreased by administration of mofezolac, the value for the former at 1200 p.p.m. being 60% of control value. When Apc gene knockout mice (APC1309 mice) were given 600 or 1200 p.p.m. mofezolac in their diet for 8 weeks, the numbers of intestinal polyps were also dose-dependently decreased, with reduction to 59% of that in the control diet group at the higher dose. Nimesulide, a COX-2 selective inhibitor used as positive control, showed similar suppressive effects on the development of ACFs in AOM-treated rats and polyps in Apc gene knockout mice. The data indicate that both COX-1 and COX-2 can contribute to intestinal tumorigenesis.

Animals↗
PubMed1988

Suppression of large intestinal cancer in F344 rats by inositol hexaphosphate.

Epidemiological data demonstrate correlations between dietary factors and the incidence of large intestinal cancer (LIC). Certain high-fiber diets are associated with a lower risk of LIC; these high-fiber diets are also rich in inositol hexaphosphate (IP6 or phytic acid). In a pilot study, we have used F344 rats to investigate the effect of sodium inositol hexaphosphate (Na-IP6) prior to (experiment I) and following injections of the carcinogen azoxymethane (AOM) (experiment II). In experiment I, rats started on 1% Na-IP6 in drinking water 1 week prior to the carcinogen treatment showed a 34.7% decrease (P less than 0.01) in LIC compared to control carcinogen treatment group. A similar reduction in the incidence of LIC was also observed in experiment II, wherein Na-IP6 supplementation was started 2 weeks following the last dose of the carcinogen. Comparison of the incidence of mitosis in the colonic crypts of the animals in different groups show that animals on AOM + IP6 demonstrate a significantly lower (P less than 0.001) mitotic rate than those receiving AOM only. Pilot studies of free radical generation demonstrate a reduction in .OH radical formation by Na-IP6. Further studies to expand this pilot data and to understand the mechanism of IP6 mediated LIC suppression are needed for it may have significance in our strategies for LIC control.

Animals↗
PubMed2003

Enhancement of colon carcinogenesis by prostaglandin E2 administration.

Although an accumulating body of evidence indicates that levels of prostaglandin E(2) (PGE(2)) in human and rodent colon cancers are higher than those in surrounding normal tissues, the precise contribution of PGE(2) to the process of colon cancer development has still been unclear. Therefore, we designed a study using a well-established azoxymethane (AOM)-induced colon carcinogenesis in male F344 rat model to investigate whether administration of exogenous PGE(2) has a real impact on colon carcinogenesis. Intraperitoneal PGE(2) injections (7.7 micro g) once a week for 25 weeks significantly increased the AOM-induced colon tumor incidence (percent rats with tumors, 92 versus 53%, P < 0.05), especially adenocarcinomas (92 versus 47%, P < 0.05), and multiplicity (number of tumors per rat, 2.8 versus 1.0, P < 0.05). PGE(2) treatment significantly increased 5-bromo-2'-deoxyuridine (BrdUrd) labeling index (11.8 versus 9.7%, P < 0.05) and reduced apoptotic index (0.34 versus 0.53%, P < 0.05) in colon cancers induced by AOM. PGE(2) exhibits its physiological functions through binding to E-prostanoid (EP) membrane receptors EP(1-4). All four types of EP receptors were detected in AOM-induced colon cancers using reverse transcription-polymerase chain reaction (RT-PCR). Our results provide evidence that PGE(2) enhances colon carcinogenesis through induction of cell proliferation and reduction of apoptosis.

Adenocarcinoma↗
PubMed2003

Effect of resistant starch on genotoxin-induced apoptosis, colonic epithelium, and lumenal contents in rats.

The effect of different doses of a type-2 resistant starch (RS) in the form of high amylose cornstarch (HAS) on the intralumenal environment and the acute-apoptotic response to a genotoxic carcinogen (AARGC) in the colon was assessed to determine if changes in lumenal conditions were associated with an enhanced apoptotic response to DNA damage. The control diet was a modified form of the AIN-76 diet containing fully digestible starch but no dietary fibre. HAS was added to the control diet at the expense of digestible starch to give 10% HAS, 20% HAS and 30% HAS. Rats were fed the different experimental diets for a period of 4 weeks, after which a single injection of azoxymethane was given to induce DNA damage in the colonic epithelium; 6 h later AARGC was measured. Other measures included fecal and cecal short chain fatty acids (SCFA) and pH, and cell proliferation in the colonic epithelium. In HAS-supplemented rats, fermentation events were significantly increased in both cecum and feces. There was a progressive decrease in pH in both the cecum and feces as the amount of HAS in the diet increased. SCFA concentrations, including butyrate, were significantly elevated by HAS with higher levels being observed in the cecum than in the feces. There was a significant increase in colonic AARGC with HAS doses of 20 and 30% (P < 0.01) but not with 10% HAS. Cell proliferation was not affected by any dose of HAS. Correlations with AARGC, independent of dietary group, were seen for fecal SCFAs and pH, suggesting that fermentation events, might explain the effect of RS on AARGC. Altering amounts of dietary RS changes fermentative activity in the colon. Increased RS is associated with enhanced AARGC. Changes in amount of fermentable substrate are capable of changing the biological response to DNA damage.

Amylose↗
PubMed2003

Meat and cancer: haemoglobin and haemin in a low-calcium diet promote colorectal carcinogenesis at the aberrant crypt stage in rats.

High intake of red meat, but not of white meat, is associated with an increased risk of colon cancer. However, red meat does not promote cancer in rodents. Haemin, added to low-calcium diets, increases colonic proliferation, and haemoglobin, added to high-fat diets, increases the colon tumour incidence in rats, an effect possibly due to peroxyl radicals. We thus speculated that haem might be the promoting agent in meat, and that prevention strategies could use calcium and antioxidants. These hypotheses were tested in rats at the aberrant crypt foci (ACF) stage at 100 days. F344 rats (n = 124) were given an injection of azoxymethane and were then randomized to 11 groups fed with low-calcium (20 micro mol/g) AIN76-based diets, containing 5% safflower oil. Haemin (0.25, 0.5 and 1.5 micro mol/g) or haemoglobin (1.5 and 3 micro mol haem/g) was added to five experimental diets, compared with a control diet without haem. Three other high-haemin diets (1.5 micro mol/g) were supplemented with calcium (250 micro mol/g), antioxidant butylated hydroxyanisole and rutin (0.05% each), and olive oil, which replaced safflower oil. Faecal water was assayed for lipid peroxidation by thiobarbituric acid reactive substances (TBARs) test, and for cytolytic activity. Haemin strikingly increased the ACF size, dose-dependently, from 2.6 to 11.4 crypts/ACF (all P < 0.001). The high-haemin diet also increased the number of ACF per colon (P < 0.001). Promotion was associated with increased faecal water TBARs and cytotoxicity. Calcium, olive oil and antioxidants each inhibited the haemin-induced ACF promotion, and normalized the faecal TBARs and cytotoxicity. The haemoglobin diets increased the number of ACF and faecal TBARs, but not the ACF size or the faecal cytotoxicity. In conclusion, dietary haemin is the most potent known ACF promoter. Haemoglobin is also a potent promoter of colorectal carcinogenesis. The results suggest that myoglobin in red meat could promote colon cancer. Diets high in calcium, or in oxidation-resistant fats, may prevent the possible cancer-promoting effect of red meat.

Animals↗
PubMed2004

Modulation by celecoxib and difluoromethylornithine of the methylation of DNA and the estrogen receptor-alpha gene in rat colon tumors.

The ability of celecoxib and alpha-difluoromethylornithine (DFMO) to modulate the DNA hypomethylation and the hypermethylation of the estrogen receptor (ER)-alpha gene in colon tumors was evaluated as potential biomarkers for chemoprevention. Colon tumors were induced in rats by azoxymethane. Celecoxib (500 mg/kg), DFMO (100, 1000 and 3000 mg/kg) or celecoxib + 1000 mg/kg DFMO were administered in the diet for 7 or 28 days prior to death at week 37. Relative to the normal colon mucosa, colon tumors contained global hypomethylated DNA but simultaneous hypermethylation of the promoter plus exon-1 region of the ER-alpha gene. Limited treatment with celecoxib (500 p.p.m. in diet) or DFMO (1000 or 3000 p.p.m. in diet) reversed the DNA hypomethylation. Administering 1000 and 3000 p.p.m. DFMO for 7-days decreased the number of methylated CpG sites in the ER-alpha gene from 5.00 +/- 0.95 to 3.83 +/- 0.75 and 1.75 +/- 0.49 these levels were further reduced to 0.50 +/- 0.26 following administration of 1000 mg/kg for 28 days. Celecoxib administered for 7 and 28 days reduced the number of methylated sites to 4.25 +/- 0.48 and 1.5 +/- 0.50. The combination containing celecoxib and DFMO reduced the number of methylated sites to 0.20 +/- 0.20 at both 7 and 28 days. In parallel with the hypermethylation of the ER-alpha gene, the mRNA expression of the gene was decreased in colon tumors and was increased by celecoxib, DFMO or the combination. Celecoxib and DFMO reversed DNA hypomethylation and the hypermethylation of the ER-alpha gene in colon tumors supporting the hypothesis that modulation of methylation is a biomarker of chemoprevention.

Animals↗
PubMed2004

Prostaglandin E receptor subtype EP(1) deficiency inhibits colon cancer development.

Prostaglandin E(2) exerts its biological activity through binding to its membrane receptors, E-prostanoid (EP) receptors. Our previous finding that lack of EP(1) receptor inhibits the early stages of colon carcinogenesis led us to investigate whether EP(1) receptor deficiency reduces colon cancer development induced by azoxymethane (AOM) using EP(1) receptor knockout mice. At 6 weeks of age 33 homozygous EP(1)-deficient (EP(1)(-/-)) mice and 28 wild-type (EP(1)(+/+)) mice were given i.p. AOM (10 mg/kg body wt) once a week for 6 weeks. At 56 weeks of age all animals were killed and intestinal tumors were examined. The results clearly indicated that lack of EP(1) receptor significantly reduced colon cancer incidence (27 versus 57%, P < 0.05) and multiplicity (0.30 versus 0.76, P < 0.05) as well as tumor volume (12.2 versus 75.6 mm(3), P < 0.05). In EP(1)(-/-) mice, silver stained nucleolar organization region protein count as cell proliferation marker was significantly reduced (1.35 versus 2.17, P < 0.001) and apoptosis was significantly increased (0.685 versus 0.077, P < 0.001) in colon tumors induced by AOM compared with those in EP(1)(+/+) mice. We confirmed that EP(1) receptor mRNA was overexpressed in colon cancers of EP(1)(+/+) mice using reverse transcription-polymerase chain reaction. These results provide strong evidence that the EP(1) receptor is of major importance for colon cancer development and it could be a new target for a mechanism-based chemoprevention strategy against colon cancer development.

Adenocarcinoma↗
PubMed2005

Modulation of aberrant crypt foci and apoptosis by dietary herbal supplements (quercetin, curcumin, silymarin, ginseng and rutin).

It is estimated that one-third of Americans use dietary herbal supplements on a regular basis. Diets rich in bioactive phytochemicals are associated with reduced risk of certain cancers, notably, colon cancer. Herbal supplements have not been directly tested as sources of bioactive cancer preventives. Hence, this study compares the ability of four herbal flavonoids (quercetin, curcumin, rutin and silymarin) and one whole herb mixture (ginseng powder) to suppress aberrant crypt foci (ACF) in an azoxymethane (AOM)-induced rat colon cancer model. Second, this study examines the effect of these herbal compounds on apoptosis and the mechanisms by which these compounds evoke apoptosis. The results of this study show that diets containing quercetin, curcumin, silymarin, ginseng and rutin decreased the number of ACFs by 4-, 2-, 1.8-, 1.5- and 1.2-fold, respectively compared with control. Histological analysis of the colon mucosa revealed that all the herbal supplements, except silymarin, induced apoptosis, with quercetin being the most potent (3x increase compared with control). Furthermore, ginseng and curcumin were region-specific in inducing apoptosis. The ability of quercetin and curcumin to modulate ACFs correlates well with their ability to induce apoptosis. Western blot analysis of caspase 9, Bax (proapoptotic) and Bcl-2 (antiapoptotic) proteins from the colon scraping suggests that quercetin and curcumin induce apoptosis via the mitochondrial pathway. Taken together, the results of this study suggest that these herbal supplements may exert significant and potentially beneficial effects on decreasing the amount of precancerous lesions and inducing apoptosis in the large intestine.

Animals↗