[Shenbai Jiedu Fang inhibits AOM/DSS-induced colorectal adenoma formation and carcinogenesis in mice via miRNA-22-mediated regulation of the PTEN/PI3K/AKT signaling pathway].

OBJECTIVE: To observe the inhibitory effect of Shenbai Jiedu Fang (SBJDF, a compound recipe of traditional Chinese herbal drugs) on chemically induced carcinogenesis of colorectal adenoma in mice and explore the role of PTEN/PI3K/AKT signaling pathway in mediating this effect. METHODS: Four-week-old male C57BL/6 mice were randomly divided into control group (n=10), AOM/DSS model group (n=20), low-dose (14 g/kg) SBJDF group (n=10) and high-dose (42 g/kg) SBJDF group (n= 10). In the latter 3 groups, the mice were treated with azoxymethane (AOM) and dextran sodium sulphate (DSS) to induce carcinogenesis of colorectal adenoma. In the two SBJDF treatment groups, SBJDF was administered daily by gavage during the modeling. The survival rate, body weight, general condition of the mice, and intestinal adenoma formation and carcinogenesis were observed. The expressions of proteins associated with the PTEN/PI3K/AKT signaling pathway in the intestinal tissue were detected using immunohistochemistry. RESULTS: Compared with those in the model group, the mice treated with SBJDF, especially at the high dose, showed a significantly lower incidence of intestinal carcinogenesis and had fewer intestinal tumors with smaller tumor volume. Pathological examination showed the occurrence of adenocarcinoma in the model group, while only low-grade and high-grade neoplasia were found in low-dose SBJDF group; the mice treated with high-dose SBJDF showed mainly normal mucosal tissues in the intestines with only a few lesions of low-grade neoplasia of adenoma. Compared with those in the control group, the mice in the model group had significantly elevated plasma miRNA-222 level (P < 0.05), which was obviously lowered in the two SBJDF groups (P < 0.01). The results of immunohistochemistry revealed that compared with the model group, the two SBJDF groups, especially the high-dose group, had significantly up-regulated expressions of PTEN, P-PTEN and GSK-3ß and down-regulated expressions of p-GSK-3 ß, PI3K, AKT, P-AKT, ß-catenin, c-myc, cyclinD1 and survivin in the intestinal tissues. CONCLUSION: SBJDF can significantly inhibit colorectal adenoma formation and carcino-genesis in mice possibly through regulating miRNA-222 and affecting PTEN/PI3K/AKT signaling pathway.

Glucosamine and Chondroitin Supplements and Risk of Colorectal Adenoma and Serrated Polyp.

BACKGROUND: Studies have shown an inverse association between use of glucosamine and chondroitin supplements and colorectal cancer risk. However, the association with the precursor lesion, colorectal adenoma and serrated polyp, has not been examined. METHODS: Analyses include 43,163 persons from the Nurses' Health Study (NHS), Health Professionals Follow-up Study (HPFS), and NHS2 who reported on glucosamine/chondroitin use in 2002 and who subsequently underwent ≥1 lower gastrointestinal endoscopy. By 2012, 5,715 conventional (2,016 high-risk) adenomas were detected, as were 4,954 serrated polyps. Multivariable logistic regression for clustered data was used to calculate OR and 95% confidence intervals (CI). RESULTS: Glucosamine/chondroitin use was inversely associated with high risk and any conventional adenoma in NHS and HPFS: in the pooled multivariable-adjusted model, glucosamine + chondroitin use at baseline was associated with a 26% (OR = 0.74; 95% CI, 0.60-0.90; P heterogeneity = 0.23) and a 10% (OR = 0.90; 95% CI, 0.81-0.99; P heterogeneity = 0.36) lower risk of high-risk adenoma and overall conventional adenoma, respectively. However, no association was observed in NHS2, a study of younger women (high-risk adenoma: OR = 1.09; 95% CI, 0.82-1.45; overall conventional adenoma: OR = 1.00; 95% CI, 0.86-1.17), and effect estimates pooled across all three studies were not significant (high-risk: OR = 0.83; 95% CI, 0.63-1.10; P heterogeneity = 0.03; overall conventional adenoma: OR = 0.93; 95% CI, 0.85-1.02; P heterogeneity = 0.31). No associations were observed for serrated polyps. CONCLUSIONS: Glucosamine/chondroitin use was associated with lower risks of high-risk and overall conventional adenoma in older adults; however, this association did not hold in younger women, or for serrated polyps. IMPACT: Our study suggests that glucosamine and chondroitin may act on early colorectal carcinogenesis in older adults.

Calcium and vitamin D supplementation and increased risk of serrated polyps: results from a randomised clinical trial.

OBJECTIVE: Serrated lesions such as sessile serrated adenomas or polyps (SSA/Ps) are important colorectal cancer precursors, but aetiological factors for these lesions are largely unknown. We aimed to determine the effects of calcium and vitamin D supplementation on the incidence of serrated polyps (SPs) in general and hyperplastic polyps and SSA/Ps specifically. DESIGN: Participants with one or more adenoma at baseline were randomised to receive 1200 mg/day of elemental calcium, 1000 IU/day of vitamin D3, both or neither agent. Treatment continued for 3 or 5 years, when risk of polyps was determined from surveillance colonoscopy (treatment phase). Outcomes after treatment ceased were also assessed (observational phase). Adjusted risk ratios (aRRs) of SPs were determined via multivariable generalised linear models. RESULTS: SPs were diagnosed in 565 of 2058 (27.5%) participants during the treatment phase and 329/1108 (29.7%) during the observational phase. In total, 211 SSA/Ps were identified during follow-up. In the treatment phase, there was no effect of either calcium or vitamin D on incidence of SSA/Ps. However, during the later observational phase, we observed elevated risks of SSA/Ps associated with calcium alone and calcium+vitamin D treatment (aRR (95% CI): 2.65 (1.43 to 4.91) and 3.81 (1.25 to 11.64), respectively). CONCLUSION: In a large multicentre chemoprevention study, we found evidence that calcium and vitamin D supplementation increased the risk of SSA/Ps. This appeared to be a late effect: 6-10 years after supplementation began. These possible risks must be weighed against the benefits of calcium and vitamin D supplementation. : Trial registration NUMBER: NCT00153816; Results.

Secondary bile acids effects in colon pathology. Experimental mice study.

PURPOSE: To assess whether deoxycholic acid (DOC) and lithocholic acid (LCA) administered in a period of six months in a concentration of 0.25% may have a carcinogenic role in mice colon. METHODS: The study used C57BL6 female mice divided into four groups. The control group received a balanced diet and the others received diets supplemented with 0.25% DOC, 0.25% LCA and 0.125% DOC+0.125% LCA, respectively. After euthanasia, the lesions found in the resected gastrointestinal tracts were stained with hematoxylin-eosin and examined microscopically. RESULTS: No gastrointestinal tract changes were observed in the control group, while hyperplastic Peyer's patches in the small intestine, flat adenomas with mild dysplasia and chronic colitis at the level of the colon were found in all three test groups. The colonic lesions prevailed in the proximal colon. The highest number of flat adenoma lesions (8), hyperplasia of Peyer's patches (25) and chronic colitis (2) were found in mice fed with diet and LCA. CONCLUSION: Precancerous or cancerous pathological lesions could not be identified. Instead, adenomatous colonic injuries occurred in a shorter period of time (six months), compared to the reported data.

Secondary bile acids effects in colon pathology. Experimental mice study

ABSTRACTPURPOSE:To assess whether deoxycholic acid (DOC) and lithocholic acid (LCA) administered in a period of six months in a concentration of 0.25% may have a carcinogenic role in mice colon.METHODS:The study used C57BL6 female mice divided into four groups. The control group received a balanced diet and the others received diets supplemented with 0.25% DOC, 0.25% LCA and 0.125% DOC+0.125% LCA, respectively. After euthanasia, the lesions found in the resected gastrointestinal tracts were stained with hematoxylin-eosin and examined microscopically.RESULTS:No gastrointestinal tract changes were observed in the control group, while hyperplastic Peyer's patches in the small intestine, flat adenomas with mild dysplasia and chronic colitis at the level of the colon were found in all three test groups. The colonic lesions prevailed in the proximal colon. The highest number of flat adenoma lesions (8), hyperplasia of Peyer's patches (25) and chronic colitis (2) were found in mice fed with diet and LCA.CONCLUSION: Precancerous or cancerous pathological lesions could not be identified. Instead, adenomatous colonic injuries occurred in a shorter period of time (six months), compared to the reported data.

Immunosuppressive effects of Pteridium aquilinum enhance susceptibility to urethane-induced lung carcinogenesis.

Pteridium aquilinum (bracken fern), one of the most important toxic plants in the world, contains the toxic norsequiterpene ptaquiloside that induces cancers in humans and farm animals. Previous studies in the laboratory demonstrated immunotoxic effects produced by ptaquiloside, which are characterized by suppression of natural killer (NK) cell activity (i.e. cytotoxicity and interferon [IFN]-γ production). However, it is unknown whether these immunosuppressive effects could contribute to carcinogenesis in situ in general because of the important function of NK cells in innate killing of tumor cells. This study assessed the impact of P. aquilinum-induced immunosuppression on urethane-induced lung cancer in C57BL/6 mice. Adult mice were treated with an extract of P. aquilinum (30 g/kg/day) by gavage once daily for 14 days, followed by gavage (5 days/week) during an 11-week period that was accompanied by treatment with urethane (1 g/kg) via once-weekly intraperitoneal injection; 20 weeks after the end of the treatment period, all lungs were evaluated. The results indicated there was a significant increase in lung nodule number as well as in multiplicity of lesions in mice treated with both P. aquilinum and urethane (PU group) compared to values in mice treated only with the urethane (U group). In addition, histologic evaluation revealed a 76% increase in the rate of lung adenomas and a 41% increase in rate of bronchiolization of alveoli in the mice from the PU group compared to levels seen in mice within the U group. Taken together, the results here show for the first time that immunosuppressive effects of P. aquilinum could increase the risk of cancer formation in exposed hosts.

Bovine milk-derived α-lactalbumin inhibits colon inflammation and carcinogenesis in azoxymethane and dextran sodium sulfate-treated mice.

Cyclooxygenase-2 is expressed early in colon carcinogenesis and plays crucial role in the progress of the disease. Recently, we found that α-lactalbumin had anti-inflammatory activity by inhibiting cyclooxygenase-2. In experiment 1, we investigated the effects of α-lactalbumin on the colon carcinogenesis initiated with azoxymethane (AOM) followed by promotion with dextran sodium sulfate (DSS) in mice. Dietary treatment with α-lactalbumin decreased fecal occult blood score at 3 days after DSS intake. α-Lactalbumin also decreased the colon tumor at week 9. In experiment 2, AOM-treated mice were sacrificed at 7 days after DSS intake. The plasma and colon prostaglandin E2 (PGE2) levels in AOM/DSS-treated mice were higher than those in the DSS-treated mice without initiation by AOM. α-Lactalbumin decreased PGE2 in both plasma and colon. These results suggest that α-lactalbumin effectively inhibited colon carcinogenesis, and the inhibition may be due to the decreased PGE2 by inhibiting cyclooxygenase-2 at cancer promotion stages.

Oral 5-fluorouracil colon-specific delivery through in vivo pellet coating for colon cancer and aberrant crypt foci treatment.

In situ coating of 5-fluorouracil pellets by ethylcellulose and pectin powder mixture (8:3 weight ratio) in capsule at simulated gastrointestinal media provides colon-specific drug release in vitro. This study probes into pharmacodynamic and pharmacokinetic profiles of intra-capsular pellets coated in vivo in rats with reference to their site-specific drug release outcomes. The pellets were prepared by extrusion-spheronization technique. In vitro drug content, drug release, in vivo pharmacokinetics, local colonic drug content, tumor, aberrant crypt foci, systemic hematology and clinical chemistry profiles of coated and uncoated pellets were examined against unprocessed drug. In vivo pellet coating led to reduced drug bioavailability and enhanced drug accumulation at colon (179.13 µg 5-FU/g rat colon content vs 4.66 µg/g of conventional in vitro film-coated pellets at 15 mg/kg dose). The in vivo coated pellets reduced tumor number and size, through reforming tubular epithelium with basement membrane and restricting expression of cancer from adenoma to adenocarcinoma. Unlike uncoated pellets and unprocessed drug, the coated pellets eliminated aberrant crypt foci which represented a putative preneoplastic lesion in colon cancer. They did not inflict additional systemic toxicity. In vivo pellet coating to orally target 5-fluorouracil delivery at cancerous colon is a feasible therapeutic treatment approach.

Kava blocks 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in association with reducing O6-methylguanine DNA adduct in A/J mice.

We previously reported the chemopreventive potential of kava against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)- and benzo(a)pyrene (BaP)-induced lung tumorigenesis in A/J mice during the initiation and postinitiation stages. In this study, we investigated the tumorigenesis-stage specificity of kava, the potential active compounds, and the underlying mechanisms in NNK-induced lung tumorigenesis in A/J mice. In the first experiment, NNK-treated mice were given diets containing kava at a dose of 5 mg/g of diet during different periods. Kava treatments covering the initiation stage reduced the multiplicity of lung adenomas by approximately 99%. A minimum effective dose is yet to be defined because kava at two lower dosages (2.5 and 1.25 mg/g of diet) were equally effective as 5 mg/g of diet in completely inhibiting lung adenoma formation. Daily gavage of kava (one before, during, and after NNK treatment) completely blocked lung adenoma formation as well. Kavalactone-enriched fraction B fully recapitulated kava's chemopreventive efficacy, whereas kavalactone-free fractions A and C were much less effective. Mechanistically, kava and fraction B reduced NNK-induced DNA damage in lung tissues with a unique and preferential reduction in O(6)-methylguanine (O(6)-mG), the highly tumorigenic DNA damage by NNK, correlating and predictive of efficacy on blocking lung adenoma formation. Taken together, these results demonstrate the outstanding efficacy of kava in preventing NNK-induced lung tumorigenesis in A/J mice with high selectivity for the initiation stage in association with the reduction of O(6)-mG adduct in DNA. They also establish the knowledge basis for the identification of the active compound(s) in kava.

Effects of selenium on Pteridium aquilinum and urethane-induced lung carcinogenesis.

The results of our previous study demonstrated that ptaquiloside, the main toxic agent found in Pteridium aquilinum, suppresses natural killer (NK) cell-mediated cytotoxicity. However, the ability of ptaquiloside to suppress the cytotoxicity of NK cells was prevented by selenium supplementation. NK cells play an important role in the innate immune response and have the ability to kill tumor cells. Therefore, we hypothesized that selenium may prevent the higher susceptibility to urethane-induced lung carcinogenesis that has been observed in mice treated with P. aquilinum. The immunosuppressive effects of ptaquiloside have been associated with a higher number of urethane-induced lung nodules in mice. Hence, we assessed the effects of P. aquilinum-induced immunosuppression on urethane-induced lung carcinogenesis in C57BL/6 mice that had been supplemented with selenium. For these experiments, mice were treated with both an aqueous extract of P. aquilinum (20 g/kg/day) and selenium (1.3 mg/kg) by gavage once daily for 14 days followed by a once-weekly intraperitoneal injection of urethane (1 g/kg) for 10 weeks that was accompanied by gavage 5 days a week. Lung adenomas in mice that had been treated with P. aquilinum plus urethane occurred with a frequency that was 44% higher than that in mice that had been treated with only urethane. In mice that had been supplemented with selenium and treated with P. aquilinum plus urethane, the occurrence of lung adenomas was reduced to 26%. These results suggest that selenium prevents the immunosuppressive effects of P. aquilinum on urethane-induced lung carcinogenesis.

Deletion of glutathione peroxidase-2 inhibits azoxymethane-induced colon cancer development.

The selenoprotein glutathione peroxidase-2 (GPx2) appears to have a dual role in carcinogenesis. While it protected mice from colon cancer in a model of inflammation-triggered carcinogenesis (azoxymethane and dextran sodium sulfate treatment), it promoted growth of xenografted tumor cells. Therefore, we analyzed the effect of GPx2 in a mouse model mimicking sporadic colorectal cancer (azoxymethane-treatment only). GPx2-knockout (KO) and wild-type (WT) mice were adjusted to an either marginally deficient (-Se), adequate (+Se), or supranutritional (++Se) selenium status and were treated six times with azoxymethane (AOM) to induce tumor development. In the -Se and ++Se groups, the number of tumors was significantly lower in GPx2-KO than in respective WT mice. On the +Se diet, the number of dysplastic crypts was reduced in GPx2-KO mice. This may be explained by more basal and AOM-induced apoptotic cell death in GPx2-KO mice that eliminates damaged or pre-malignant epithelial cells. In WT dysplastic crypts GPx2 was up-regulated in comparison to normal crypts which might be an attempt to suppress apoptosis. In contrast, in the +Se groups tumor numbers were similar in both genotypes but tumor size was larger in GPx2-KO mice. The latter was associated with an inflammatory and tumor-promoting environment as obvious from infiltrated inflammatory cells in the intestinal mucosa of GPx2-KO mice even without any treatment and characterized as low-grade inflammation. In WT mice the number of tumors tended to be lowest in +Se compared to -Se and ++Se feeding indicating that selenium might delay tumorigenesis only in the adequate status. In conclusion, the role of GPx2 and presumably also of selenium depends on the cancer stage and obviously on the involvement of inflammation.

Pituitary microadenoma treated with antipsychotic drug aripiprazole.

Male patient 24 years old with a pituitary microadenoma and mental and behavioural disorders due to multiple drug use and use of other psychoactive substances (cocaine, cannabis and alcohol) were treated with haloperidol (dopamine receptor blocker) 10 mg daily. In the last control, the patient presented mammary hypertrophy; laboratory testing and brain magnetic resonance imaging (MRI) was performed, reporting the presence of a pituitary microadenoma syndrome with hormonal alteration (Prolactin levels 28.4 ng/ml). Haloperidol, carbamazepine and levomepromazine were then discontinued. He was started on aripiprazole 15 mg po daily for 4 days; the dosage was then increased to 30 mg po daily, with Valproic Acid 500 mg po tid. After 3 weeks on aripiprazole, the mammary hypertrophy that had increased in the patient had resolved. After 10 weeks follow up of prolactin revealed a normal level, at 4.33 ng/ml. Insomnia, aggressiveness, irritability, visual, tactile and auditory hallucinations remained absent after treatment with aripiprazole which is not a first line drug in multiple drug use patient with psychosis. We also consider the correlation of drug use in patient with psychosis, haloperidol treatment, pituitary microadenoma syndrome, hyperprolactinemia, and dopamine D2- receptor partial agonist aripiprazole treatment. This article also summarizes some relevant patents.

Aloe vera non-decolorized whole leaf extract-induced large intestinal tumors in F344 rats share similar molecular pathways with human sporadic colorectal tumors.

Aloe vera is one of the most commonly used botanicals for various prophylactic and therapeutic purposes. Recently, NTP/NCTR has demonstrated a dose-dependent increase in large intestinal tumors in F344 rats chronically exposed to Aloe barbadensis Miller (Aloe vera) non-decolorized whole leaf extract (AVNWLE) in drinking water. The morphological and molecular pathways of AVNWLE-induced large intestinal tumors in the F344 rats were compared to human colorectal cancer (hCRC) literature. Defined histological criteria were used to compare AVNWLE-induced large intestinal tumors with hCRC. The commonly mutated genes (Kras, Ctnnb1, and Tp53) and altered signaling pathways (MAPK, WNT, and TGF-ß) important in hCRC were evaluated within AVNWLE-induced large intestinal tumors. Histological evaluation of the large intestinal tumors indicated eight of twelve adenomas (Ads) and four of twelve carcinomas (Cas). Mutation analysis of eight Ads and four Cas identified point mutations in exons 1 and 2 of the Kras gene (two of eight Ads, two of four Cas), and in exon 2 of the Ctnnb1 gene (three of eight Ads, one of four Cas). No Tp53 (exons 5-8) mutations were found in Ads or Cas. Molecular pathways important in hCRC such as MAPK, WNT, and TGF-ß signaling were also altered in AVNWLE-induced Ads and Cas. In conclusion, the AVNWLE-induced large intestinal tumors in F344 rats share several similarities with hCRC at the morphological and molecular levels.

Folic acid in obstetric practice: a review.

UNLABELLED: Folic acid is one of the B complex vitamins and is now recognized as a major component of the periconceptional care of women in the reproductive age group. Deficiency of folic acid can lead to neural tube defects in the fetus and megaloblastic anemia in the mother. Due to its lower bioavailability from natural foods, many countries have adopted mandatory folic acid food fortification programs. Although these programs have been a public health triumph in reducing the burden of neural tube defects, there have been growing concerns about the role played by folic acid supplementation in the rising colon cancer rates over the past decade. The majority of the evidence available to date is reassuring, and until further long-term population as well as laboratory studies are completed, folic acid will continue to play a vital role in early pregnancy care. It is important for healthcare professionals to be aware of the recent evidence that has accumulated, suggesting higher folic acid requirements in certain groups of women and offer correct advice on the use of folic acid supplements. This review looks at some of the existing evidence on folic acid supplementation and summarizes the recommendations on the use of folic acid supplements by obstetricians, family physicians, and others providing prenatal care. TARGET AUDIENCE: Obstetricians and Gynecologists, Family physicians. LEARNING OBJECTIVES: After completing this CME activity, physicians should be better able to evaluate the need for folic acid supplementation in various patient groups to lower the risk of neural tube defects due to folate deficiency; recommend common, natural and fortified food sources rich in folic acid; and distinguish the effects of folate deficiency in the mother and fetus.

Folic acid supplementation and colorectal cancer risk: a meta-analysis.

AIM: This meta-analysis aims to determine the effect of folic acid supplementation on colorectal cancer risk. METHOD: A structured search of the MEDLINE, EMBASE, Cochrane and CINAHL databases was undertaken in July 2008. All published full text English language articles were searched that included a randomized or pseudo-randomized comparison of subjects who received folate vs subjects who did not in relation to their risk of adenoma or advanced adenomatous lesions, including colorectal cancer. A weighted treatment effect (using fixed effects) was calculated across trials. RESULTS: Overall, the risk of an adenomatous lesion was not increased (odds ratio 1.09, 95% confidence interval 0.93-1.28) among patients who received folate supplementation for up to 3 years; however, for those who received folate for over 3 years, the risk of an adenomatous lesion was increased (odds ratio 1.35, 95% confidence interval 1.06-1.70). The risk associated with treatment was the highest for the occurrence of an advanced lesion (odds ratio 1.50, 95% confidence interval 1.06-2.10). There was no significant statistical heterogeneity in the analyses. CONCLUSION: At the 3-year colonoscopic follow up, folate supplementation had no effect on adenoma recurrence overall. While colonic surveillance beyond 3 years revealed an increased risk of colorectal adenoma, especially advanced adenoma, among those participants randomized to the folate group. This meta-analysis challenges the results from epidemiological studies that folate status is inversely related to the risk of developing colorectal cancer.

Uracil misincorporation into DNA and folic acid supplementation.

BACKGROUND: Folate deficiency decreases thymidylate synthesis from deoxyuridylate, which results in an imbalance of deoxyribonucleotide that may lead to excessive uracil misincorporation (UrMis) into DNA during replication and repair. OBJECTIVE: We evaluated the relation between UrMis in different tissues and the effect of folate supplementation on UrMis. DESIGN: We analyzed UrMis concentrations in rectal mucosa (n = 92) and white blood cells (WBCs; n = 60) among individuals randomly assigned to receive supplementation with 1 mg folate/d or placebo, who were then evaluated for colorectal adenoma recurrence. RESULTS: As expected, total homocysteine was significantly lower among the study participants who received active folate treatment (Wilcoxon's P = 0.003) than among those in the placebo group. The median UrMis concentration in rectal mucosa and WBCs among individuals treated with folate was not significantly lower than that in those who received placebo (Wilcoxon's P = 0.17). UrMis concentrations in both rectal mucosa and WBCs did not correlate significantly with folate measured in plasma and red blood cells. UrMis in rectal mucosa was marginally associated with an increased risk of adenoma recurrence (odds ratio per SD: 1.43; 95% CI: 0.91, 2.25). CONCLUSIONS: UrMis measurements in WBCs are not a robust surrogate for UrMis measurements in the rectal mucosa (Spearman correlation coefficient = 0.23, P = 0.08). Furthermore, folate supplementation in an already replete population (half treated with folic acid supplements and all exposed to folic acid fortification of the food supply) was not significantly associated with reduced UrMis in rectal mucosa cells or WBCs. Large-scale studies are needed to evaluate whether excessive UrMis concentrations are an important risk factor for colorectal neoplasia. This trial was registered at clinicaltrials.gov as NCT00272324.

Dietary tricin suppresses inflammation-related colon carcinogenesis in male Crj: CD-1 mice.

The flavone 4',5,7-trihydroxy-3',5'-dimethoxyflavone (tricin) present in rice, oats, barley, and wheat exhibits antigrowth activity in several human cancer cell lines and anti-inflammatory potential. However, the chemopreventive activity has not yet been elucidated in preclinical animal models of colorectal cancer. This study was designed to determine whether dietary tricin exerts inflammation-associated colon carcinogenesis induced by azoxymethane and dextran sulfate sodium in mice. Male Crj: CD-1 mice were initiated with a single i.p. injection of azoxymethane (10 mg/kg body weight) and followed by a 1-week exposure to dextran sulfate sodium (1.5%, w/v) in drinking water to induce colonic neoplasms. They were then given the experimental diet containing 50 or 250 ppm tricin. The experiment was terminated at week 18 to determine the chemopreventive efficacy of tricin. In addition, the effects of dietary tricin on the expression of several inflammatory cytokines, including tumor necrosis factor (TNF)-alpha, were assayed. The development of colonic adenomas and adenocarcinomas was significantly reduced by feeding with 50 and 250 ppm tricin, respectively. Dietary tricin also significantly reduced the proliferation of adenocarcinoma cells as well as the numbers of mitoses/anaphase bridging in adenocarcinoma cells. The dietary administration with tricin significantly inhibited the expression of TNF-alpha in the nonlesional cypts. Our findings that dietary tricin inhibits inflammation-related mouse colon carcinogenesis by suppressing the expression of TNF-alpha in the nonlesional cyrpts and the proliferation of adenocarcinomas suggest a potential use of tricin for clinical trials of colorectal cancer chemoprevention.

Simultaneous exposure to dietary acrylamide and corn oil developed carcinogenesis through cell proliferation and inhibition of apoptosis by regulating p53-mediated mitochondria-dependent signaling pathway.

To investigate whether simultaneous exposure to acrylamide (ACR) and long-term dietary corn oil induces colon cancer by inhibiting the tumor suppressor gene p53-mediated mitochondria-dependent apoptosis in rats. Male Sprague-Dawley rats were given intraperitoneal injections of ACR at dose of 10 mg/kgbw and diets supplemented with 10% corn oil for 8 wks; and then rats were still fed with diets supplemented with 10% oil for other 48 wks. Colonic aberrant crypt foci (ACF) and tumors, including adenomas and carcinomas, were examined at 12, 24, 36, 48 week post ACR-exposure. Colonic apoptosis and cell proliferation, expression of Wild type (wt) p53, Bcl-2, Bax and caspase-3, were detected at 48 week post ACR-exposure. ACF was found at 12 week and colon cancer invasion was found at 48 week in ACR rats on long-term dietary corn oil. Apoptosis was decreased and cell proliferation was increased in colonic mucosa in ACR-treated rats on dietary corn oil compared to vehicle rats on basal diet (P < 0.05). In ACR rats on dietary corn oil, mitochondrial wt p53 was significantly inhibited through decreased mitochondrial localization of wt p53 and increased cytosolic p53, resulting in the up-regulation of Bcl-2 and the down-regulation of Bax in the mitochondria, also inhibition of the release of cytochrome-c from the mitochondria into the cytosol and protein level of caspase-3 (P < 0.05). Results suggest that simultaneous exposure to ACR and long-term dietary corn oil induces development of colon cancer partly by inhibiting the tumor suppressor gene p53-mediated mitochondria-dependent apoptosis.

Lung cancer inhibitory effect of epigallocatechin-3-gallate is dependent on its presence in a complex mixture (polyphenon E).

Green tea has been shown to exhibit cancer-preventive activities in preclinical studies. However, (-)-epigallocatechin-3-gallate (EGCG) alone was shown to be ineffective in preventing lung tumorigenesis in mice by aerosol administration. In this study, Polyphenon E and Polyphenon E without EGCG were administered by aerosol delivery to A/J mice 2 weeks after carcinogen treatment and continuing daily throughout the remainder of the study (20 weeks). An improved aerosol delivery system with a custom-built atomizer, an efficient solvent remove system, and a nose-only exposure chamber was used to provide aerosols with stable size distribution. There were no significant differences in the size distributions of Polyphenon E and Polyphenon E without EGCG. With a relatively low dose level (4.19 mg/kg), Polyphenon E decreased tumor multiplicity by 53%, whereas Polyphenon E without EGCG at the same dose failed to inhibit lung carcinogenesis. These results indicate that aerosol administration can be an effective approach in chemoprevention study, and aerosolized Polyphenon E can significantly inhibit pulmonary adenoma formation and growth in A/J mice. Furthermore, in aerosolized form, EGCG, which is thought to be the most active component of Polyphenon E, has to be present with other tea catechins to show chemopreventive activity on lung tumorigenesis.