Induced Rat Colon Carcinogenesis Research Articles

Arthrospira (Spirulina) platensis feeding reduces the early stage of chemically induced rat colon carcinogenesis.

Colorectal cancer is the third most diagnosed cancer worldwide and linked to dietary/lifestyle factors. Arthrospira (Spirulina) platensis (AP) contains bioactive compounds with beneficial effects in vivo/in vitro. We evaluated the effects of AP feeding against 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis. Male Sprague Dawley rats were given subcutaneous injections of DMH (4 × 40 mg/kg body weight) (G1-G3) or vehicle (G4-G5) twice a week (weeks 3-4). During weeks 1-4, animals were fed a diet containing 1 % (G2) or 2 % (G3-G4) AP powder (w/w). After this period, all groups received a balanced diet until week 12. Some animals were euthanised after the last DMH injection (week 4) for histological, immunohistochemical (Ki-67, γ-H2AX and caspase-3) and molecular analyses (real time-PCR for 91 genes), while other animals were euthanised at week 12 for preneoplastic aberrant crypt foci (ACF) analysis. Both AP treatments (G2-G3) significantly decreased the DMH-induced increase in γ-H2AX (DNA damage) and caspase 3 (DNA damage-induced cell death) in colonic crypts at week 4. In addition, Cyp2e1 (Drug metabolism), Notch1, Notch2 and Jag1 genes (Notch pathway) and Atm, Wee1, Chek2, Mgmt, Ogg1 and Xrcc6 genes (DNA repair) were also down-regulated by 2 % AP feeding (G3) at week 4. A significant reduction in ACF development was observed in both AP-treated groups (G2-G3) at week 12. In conclusion, findings indicate that AP feeding reduced acute colonic damage after DMH, resulting in fewer preneoplastic lesions. Our study provided mechanistic insights on dietary AP-preventive effects against early colon carcinogenesis.

Protective effects of rosmarinic acid against azoxymethane-induced colorectal cancer in rats.

Colorectal cancer (CRC) incidence is increasing gradually and has been become one of the most common cancers worldwide. Hence, it is important to discover cheap, naturally occurring compounds to be effective in suppressing the devastating effect of colon-related tumors. Rosmarinic acid (RA), one of the compounds of plant origin, possesses attractive features for use as an agent for cancer prevention and treatment. This study investigated the ability of RA to prevent azoxymethane (AOM)-induced rat colon carcinogenesis by evaluating the effect of RA on tumor formation and circulatory oxidant-antioxidant status. Moreover, plasma levels of adiponectin (APN) monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) were detected by enzyme linked immunosorbent assay. The animals were divided into three groups: Control, AOM, and AOM + RA. Rats were fed a modified pellet diet (15.8% peanut oil was added to the standard diet) during the experimental period. Colon cancer was formed by applying 15 mg/kg AOM intraperitoneal once a week for 4 weeks in both the CRC group and AOM + RA group. Besides AOM, AOM + RA group received 5 mg/kg body weight RA orally every day during the study. The results showed that adenocarcinoma rates formed87.5% ofthe AOM group. With treatment of RA, a reduction in the incidence of adenocarcinoma was observed in the AOM + RA group. The plasma MCP-1, IL-6, and TO levels were significantly higher, APN and TAS levels were significantly lower in the AOM group with respect tocontrols. In addition, there was a significant increase in TAS levels in the RA treatment group compared to the AOM group. These findings suggested that RA may be beneficial in preventing AOM-induced colon carcinogenesis formation.

Preventive and Tumor-Suppressive Effects of Lactobacillus Paracasei X12 in Rat Model of Colorectal Cancer.

The paper in hand seeks to evaluate the tumor-suppressive and apoptotic effects of L. paracasei X12 in 1, 2-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. The rats were divided into three groups (n = 8-12 per group); L. paracasei X12 was administrated to these animals for forty weeks. The findings of this study indicated that L. paracasei X12 administration prevented severe weight loss in DMH-treated rats. It was also determined that L. paracasei X12 administration could prevent the neoplasia incidence, cell proliferation and it also could suppress the tumors’ growth. Additionally, a significant improvement was observed in apoptosis indexes and cell proliferation in probiotic-treated rats. In conclusion, this study provides insights into the therapeutic potential of L. paracasei X12 with emphasis on the issue that modulation of apoptosis pathway could leave beneficial effects in the prevention and suppression of colorectal cancer (CRC). However, further studies are in support to clarify the mechanisms involved in the tumor-suppressive effect of probiotics.

Celecoxib Therapy Attenuates Oxidative Stress During Chemically Induced Rat Colon Carcinogenesis

Abstract Reactive oxygen species (ROS), byproducts of aerobic metabolism, are increased in many types of cancer cells. Increased endogenous ROS lead to adaptive changes and may play pivotal roles in tumorigenesis, metastasis, and resistance to chemotherapy and radiation . This study aimed to asses oxidative stress markers during chemically-induced colon carcinogenesis in rats treated with 1,2-dimethylhydrazine dihydrochloried (DMH) for 24 weeks, with or without the treatment with a specific cyclooxygenase-2 inhibitor drug (celecoxib). A significant increase was recorded in the activity of antioxidant enzyme such as superoxide dismutase (SOD) and catalase (CAT), and in other oxidative stress markers such as nitric oxide (NO), reduced glutathione (GSH) levels and total antioxidant capacity (TAC) in rats treated with DMH only. However lipid peroxidation (LPO) showed a significant decrease in all markers. In celecoxib co-treated rats, all parameters showed a significant decrease except for lipid peroxidation which showed a significant increase. In conclusion, co-treatment of celecoxeb during rat colon carcinogenesis has a positive effect on redox imbalance during rat colon carcinogenesis, an implication which could possibly by of importance to colon cancer patients.

Chemopreventive efficacy of different doses of Ferula asafoetida oleo-gum-resin against 1,2-dimethylhydrazine (DMH) induced rat colon carcinogenesis

Colon cancer is the third most common malignant neoplasm in the world and it remains an important cause of deaths, especially in western countries. Its etiology is known to be a combination of hereditary, environmental, dietary factors and lack of physical activity. Chemoprevention through dietary intervention is an emerging option to reduce mortality due to colon cancer. The present study was aimed to investigate the chemopreventive potential of different doses of Ferula asafoetida oleo-gum-resin on 1,2-dimethylhydrazine (DMH) induced rat colon carcinogenesis by evaluating tumor multiplicity, tumor incidence, and tumor size, Serum total sialic acid levels as well as histoarchitecture of colons of rats subjected to various treatment. Rats were randomly divided into six groups. Group I rats served as control. Group 2 rats received DMH (30 mg/kg body weight (bw)) for 16 weeks. Group 3-5 animals received asafoetida daily at a dose level of 5mg/100gm bw, 10mg/100gm bw and 20mg/100gm bw respectively along with weakly DMH injections. Group 6 rats received asafoetida daily (20mg/100g bw daily) for 16 weeks. Increased tumor incidence and multiplicity was observed in DMH treated rats which were decreased with asafoetida supplementation. Asafoetida at the dose of 10mg/100gm bw had shown profound beneficial effects by exhibiting near normal Total Sialic Acid levels and well-preserved colon histology. These findings suggest that asafoetida dose 10mg/100g bw is minimum dose with maximum protection for colon cancer.

Cell Cycle Regulation and Apoptotic Cell Death in Experimental Colon Carcinogenesis: Intervening with Cyclooxygenase-2 Inhibitors

Relative imbalance in the pathways regulating cell cycle, cell proliferation, or cell death marks a prerequisite for neoplasm. C-phycocyanin, a biliprotein from Spirulina platensis and a selective COX-2 inhibitor along with piroxicam, a traditional nonsteroidal antiinflammatory drug was used to investigate the role of cell cycle regulatory proteins and proinflammatory transcription factor NFκB in 1,2-dimethylhydrazine dihydrochloride (DMH)-induced rat colon carcinogenesis. Cell cycle regulators [cyclin D1, cyclin E, cyclin dependent kinase 2 (CDK2), CDK4, and p53], NFκB (p65) pathway, and proliferating cell nuclear antigen (PCNA) were evaluated by gene and protein expression, whereas apoptosis was studied by terminal deoxynucleotidyl transferase dUTP nick end labeling and apoptotic bleb assay. Molecular docking of ligand protein interaction was done to validate the in vivo results. Cyclin D1, cyclin E, CDK2, and CDK4 were overexpressed in DMH, whereas piroxicam and c-phycocyanin promoted the cell cycle arrest by downregulating them. Both drugs mediated apoptosis through p53 activation. Piroxicam and c-phycocyanin also stimulated antiproliferation by restraining PCNA expression and reduced cell survival via inhibiting NFκB (p65) pathway. Molecular docking revealed that phycocyanobilin (a chromophore of c-phycocyanin) interact with DNA binding site of NFκB. Inhibition of cyclin/CDK complex by piroxicam and c-phycocyanin affects the expression of p53 in colon cancer followed by downregulation of NFκB and PCNA levels, thus substantiating the antineoplastic role of these agents.

Effect of sinapic acid on 1,2 dimethylhydrazine induced aberrant crypt foci, biotransforming bacterial enzymes and circulatory oxidative stress status in experimental rat colon carcinogenesis.

This study was aimed to investigate the effect of sinapic acid (SA) on 1,2-dimethylhydrazine (DMH) induced experimental rat colon carcinogenesis. Rats were assorted into six groups, group 1 served as control, group 2 received SA (80 mg/kg b.w.) post orally every day until the end of the experimental period of 16 weeks, groups 3-6 rats were injected DMH (20 mg/kg b.w.) subcutaneously once a week for first four weeks. In addition, groups 4-6 rats received different doses of SA (20, 40 and 80 mg/kg b.w.). Our results showed that DMH induced rats revealed significantly increased ACF development and multiplicity, which were significantly inhibited on supplementation with SA. Moreover, elevated levels/activities of circulatory oxidative stress markers, faecal and colonic mucosal bacterial enzymes were observed in DMH exposed rats, which were diminished on supplementation with SA. Overall, our findings revealed that supplementation with SA offers significant protection against DMH induced rat colon carcinogenesis and the effect of SA at the dose of 40 mg/kg b.w. was more pronounced as compared to the other two doses. (Tab.5, Fig. 3, Ref. 46)

Rosmarinic acid inhibits DMH-induced cell proliferation in experimental rats.

Colon cancer is one of the most common cancers in both men and women. The present study is an effort to unravel the anticarcinogenic effects of rosmarinic acid (RA) in 1,2-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. Administration of DMH induces multiple tumors in the rat colon, which mimics human colon cancer. Male Wistar rats were divided into six groups and fed a high-fat diet. Group 1 served as control, group 2 rats were given RA [5 mg/kg body weight (b.w.)] orally every day for a total period of 30 weeks, and groups 3-6 were given weekly injections of DMH (20 mg/kg b.w. subcutaneous) once a week in the groin for the first 15 weeks. In addition to DMH, groups 4-6 received RA at a dose of 5 mg/kg b.w. during the initiation and postinitiation stages, and also throughout the entire study period. Colon tissues were examined histologically; further, the extent of oxidative stress was assessed by measuring lipid peroxidation and antioxidant levels in the colonic mucosa of rats. Macroscopic and microscopic tumors were identified in all the groups that received DMH. The results revealed that supplementation with RA significantly inhibited the tumor formation and tumor multiplicity in DMH-treated rats. RA supplementation to DMH-administered rats significantly reduced the cell proliferation markers, namely, argyrophilic nucleolar organizing regions as well as proliferative cell nuclear antigen labeling index. In addition, RA supplementation reduces the expressions of tumor necrosis factor-α, interlukin-6, and cyclooxygenase-2, and modulates the expression of p65. The above findings clearly underline the chemopreventive efficacy of RA against DMH-induced colon carcinogenesis.

Chemopreventive effect of sinapic acid on 1,2-dimethylhydrazine-induced experimental rat colon carcinogenesis

Sinapic acid (SA) is a naturally occurring phenolic acid found in various herbal plants which is attributed with numerous pharmacological properties. This study was aimed to investigate the chemopreventive effect of SA on 1,2-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. Rats were treated with DMH injections (20 mg kg(-1) bodyweight (b.w.) subcutaneously once a week for the first 4 consecutive weeks and SA (20, 40 and 80 mg kg(-1) b.w.) post orally for 16 weeks. At the end of the 16-week experimental period, all the rats were killed, and the tissues were evaluated biochemically. Our results reveal that DMH alone treatment decreased the levels/activities of lipid peroxidation by-products such as thiobarbituric acid reactive substances, conjugated dienes and antioxidants such as superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase and reduced glutathione in the intestine and colonic tissues which were reversed on supplementation with SA. Moreover, the activities of drug-metabolizing enzymes of phase I (cytochrome P450 and P4502E1) were enhanced and those of phase II (glutathione-S-transferase, DT-diaphorase and uridine diphosphate glucuronosyl transferase) were diminished in the liver and colonic mucosa of DMH alone-treated rats and were reversed on supplementation with SA. All the above changes were supported by the histopathological observations of the rat liver and colon. These findings suggest that SA at the dose of 40 mg kg(-1) b.w. was the most effective dose against DMH-induced colon carcinogenesis, and thus, SA could be used as a potential chemopreventive agent.

Oral supplementation with troxerutin (trihydroxyethylrutin), modulates lipid peroxidation and antioxidant status in 1,2-dimethylhydrazine-induced rat colon carcinogenesis

The present study was aimed to investigate the chemopreventive potential of troxerutin on 1,2-dimethylhydrazine (DMH) induced rat colon carcinogenesis by evaluating the antioxidant and lipid peroxidation (LPO) status. Rats were randomly divided into six groups. Group I rats served as control. Group II rats received troxerutin (50mg/kgb.w., p.o.) for 16 weeks. Groups III–VI rats received subcutaneous injections of DMH (20mg/kgb.w., s.c.) once a week, for the first 4 weeks. In addition to DMH, groups IV–VI rats received troxerutin at the doses of 12.5, 25 and 50mg/kgb.w., respectively. In DMH treated rats, our results showed decreased activities of antioxidants and increased levels of LPO in the liver. Moreover, LPO and antioxidants in the colon were found to be significantly diminished in DMH the treated rats. Furthermore, enhanced activity of colonic vitamin C and vitamin E levels were observed in DMH alone treated rats (group III), which was significantly reversed on troxerutin supplementation. Troxerutin at the dose of 25mg/kgb.w. had shown profound beneficial effects by exhibiting near normal biochemical profile and well-preserved colon histology as compared to the other two tested doses (12.5 and 50mg/kgb.w.). These findings suggest that troxerutin could serve as a novel agent for colon cancer chemoprevention.

Synergistic and individual effects of umbelliferone with 5-fluorouracil on tumor markers and antioxidant status of rat treated with 1,2-dimethylhydrazine

PurposeColorectal cancer (CRC) is among the most common malignancies worldwide. Early diagnosis of the progressive tumor disease and control of the effect of therapy in colorectal carcinoma are most frequently performed. MethodsThe purpose of this present work was to evaluate the synergistic responses of a novel chemopreventive combination regimen namely 5-FU and natural coumarin family, UMB to assess the serum tumor markers CEA, CA 19-9 and CA 72-4 for colorectal carcinoma is described according to recently formulated guidelines, in addition of antioxidant and lipid peroxidation status in the serum of 1,2-dimethylhydrazine induced rat colon carcinogenesis. ResultsAdministration of DMH resulted in decreased serum levels of antioxidants such as GST, SOD, CAT, GPx, GR, GSH and lipid peroxidation end products such as TBARS, LOOH and CD with concomitant increase in the levels of colon cancer specific serum markers like CEA, CA 19-9 and CA 72-4 levels. Administration of UMB alone and combined forms of UMB with 5-FU to the colon cancer-bearing rats significantly attenuated these alterations which indicates the anticancer effect that was further confirmed by histopathological analysis. ConclusionsOverall, these findings substantiate the synergistic potential of UMB with 5-FU against chemically-induced colon cancer in rats.

Inhibitory Effect of a Standardized Pomegranate Fruit Extract on Wnt Signalling in 1, 2-Dimethylhydrazine Induced Rat Colon Carcinogenesis

De-regulation of Wnt signalling is increasingly being implicated in both experimental and human carcinogenesis including colon cancer. Our goal was to identify possible dietary agents that block Wnt signalling as a step toward investigating new strategies for suppression of colon cancer. Pomegranate extract has emerged as an intriguing candidate due to its polyphenolic content. We used a 1,2-dimethylhydrazine dihydrochloride (DMH)-induced rat colon carcinogenesis model to investigate the expression pattern of the main key players in Wnt signalling by reverse transcription polymerase chain reaction (RT-PCR) analysis. Our results showed that many Wnt-target genes, e.g., Wnt5a, frizzled receptor (FRZ)-8, β-catenin, T cell factor/lymphoid enhancer binding protein (Tcf4/Lef1), c-myc and cyclin D1, were up-regulated whereas adenomatous polyposis coli (APC) and axin1 exhibited down-regulation in colonic tissues of our DMH-colon cancer group compared with the normal group. Standardized pomegranate extract minimised all the aberrant alterations observed in the studied Wnt genes in colonic tissues of the DMH+pomegranate group as compared with the DMH-induced colon cancer group. This effect was also confirmed by the normalization of survival rate, inhibition of tumour incidence and a reduction of serum tumour marker carcinoembryonic antigen (CEA) level. Histopathological observations provided supportive evidence for the biochemical and molecular analyses. Standardized pomegranate extract holds great promise in the field of colon cancer prevention by dietary agents.

Açaí (Euterpe olecareae Martius) intake and its protective effect against 1,2-DMH-induced rat colon carcinogenesis

Background Acai (Euterpe olecareae Martius) is an important crop consumed in Brazil that gained attention due to its potential antioxidant and anti-inflammatory properties. Various studies have shown that this exotic fruit may reduce the risk of many diseases, including cancer. The present study investigated the beneficial potential of acai extract intake on the 1,2-dimethylhydrazine (DMH)induced rat colon carcinogenesis.

Synergistic and individual effects of umbelliferone with 5-flurouracil on the status of lipid peroxidation and antioxidant defense against 1, 2-dimethylhydrazine induced rat colon carcinogenesis

5-Fluorouracil (5-FU) is one of the widely used chemotherapeutic drugs targeting various cancers including colon cancer, but its chemoresistance remains as a major obstacle in clinical settings. Towards this goal, we evaluated the in vivo efficacy of umbelliferone (UMB) with 5-flurouracil (5-fu) against 1, 2-dimethylhydrazine (DMH) induced colon carcinogenesis in rats. Rats were divided into seven groups of six rats each. Rats in group 1 received high fat diet and served as control, group 2 rats received high fat diet with DMH (20mg/kg body weight) once a week subcutaneously for the first 15weeks which represent the colon cancer bearing rats. Group 3 rats received umbelliferone via intragastric injection at a daily dose of 30mg/kg body weight for 30weeks every day. Groups 4–7 rats received high fat diet with DMH (20mg/kg body weight) as in group 2. In addition group 4 rats (initiation) received UMB starting 1week before 1st DMH injection and continued till the end of last DMH injection, group 5 rats (post-initiation) received UMB after 1 week of last DMH injection and continued till the end of the experimental period, group 6 rats (Entire period) received UMB throughout the experimental period. Group 7 cancer bearing rats received 5-flurouracil (100mg/kg body weight) once a week intravenously for first 4weeks and UMB was given as in group 6 throughout the experimental period of 30 weeks Levels of glutathione-s-transferase (GST), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), glutathione reductase (GR) and reduced glutathione (GSH) decreased following DMH treatment, and also the levels of lipid peroxidation end products like thiobarbituric acid substances (TBARS), lipid hydroperoxides (LOOH) and conjugated dines (CD) were significantly decreased in DMH-treated rats. Administration of UMB alone and combined effect of UMB with 5-Fu significantly reversed these activities to near normal, which concludes the anti-carcinogenic efficacy of UMB. This effect was further confirmed by histopathological studies and finally proved that UMB as an effective and potential chemotherapeutic agent against DMH-induced colon carcinogenesis.

Modulatory efficacy of rosmarinic acid on premalignant lesions and antioxidant status in 1,2-dimethylhydrazine induced rat colon carcinogenesis

Colorectal cancer is one of the leading causes of cancer related deaths in Western countries and is becoming increasingly common in Asia. Rosmarinic acid (RA), one of the major components of polyphenol possesses attractive remedial features. The purpose of this study is to investigate the possible chemopreventive mechanism of action of RA against 1,2-dimethylhydrazine (DMH) induced rat colon carcinogenesis by evaluating the circulatory antioxidant status and colonic bacterial enzymes activities. Additionally, we analyzed the aberrant crypt foci (ACF) formation and multiplicity in the colon of experimental groups. Wistar male rats were divided into six groups. Group 1 was control rats, group 2 rats received RA (10mg/kg b.w., p.o. everyday), rats in groups 3–6 received DMH (20mg/kg b.w., s.c.) for the first 4 weeks. In addition to DMH, groups 4–6 received 2.5, 5, and 10mg/kg b.w. RA respectively. The results revealed that supplementation with RA significantly reduced the formation of ACF and ACF multiplicity in DMH treated rats. Moreover RA supplementation prevented the alterations in circulatory antioxidant enzymes and colonic bacterial enzymes activities. Overall, our results showed that all three doses of RA inhibited carcinogenesis, though the effect of the intermediary dose of 5mg/kg b.w. was more pronounced.

The effect of rosmarinic acid on 1,2-dimethylhydrazine induced colon carcinogenesis

This study was carried out to investigate the chemopreventive potential of rosmarinic acid (RA) against 1,2-dimethylhydrazine (DMH) induced rat colon carcinogenesis by evaluating the effect of RA on tumour formation, antioxidant enzymes, cytochrome P450 content, p-nitrophenol hydroxylase and GST activities. Rats were divided into six groups and fed modified pellet diet for the entire experimental period. Group 1 served as control, group 2 received RA (10 mg/kgb.w.). Groups 3-6 were induced colon cancer by injecting DMH (20 mg/kgb.w.) subcutaneously once a week for the first four weeks (groups 3-6). In addition, RA was administered at the doses of 2.5, 5 and 10 mg/kgb.w. to groups 4-6 respectively. DMH treated rats showed large number of colonic tumours; decreased lipid peroxidation; decreased antioxidant status; elevated CYP450 content and PNPH activities; and decreased GST activity in the liver and colon. Supplementation with RA (5 mgkg/b.w.) to DMH treated rats significantly decreased the number of polyps (50%); reversed the markers of oxidative stress (21.0%); antioxidant status (38.55%); CYP450 content (29.41%); and PNPH activities (21.9%). RA at the dose of 5 mg/kgb.w. showed a most pronounced effect and could be used as a possible chemopreventive agent against colon cancer.

Abnormal Savda Munziq, an Herbal Preparation of Traditional Uighur Medicine, May Prevent 1,2‐dimethylhydrazine‐Induced Rat Colon Carcinogenesis

The study tried to assess the chemoprotective effect of abnormal Savda Munziq (ASMq) on 1,2-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. Male F344 rats were randomized into eight groups: Group 1 was served as control, no DMH injection was given and treated daily with normal saline. Rats in Groups 2–8 were given a single intraperitoneal injection of DMH (20 mg/kg body weight) at the beginning of the study. Group 2 was served as negative control, administered with normal saline until the end of the experiment after the single DMH injection. Groups 3–5 were served as pretreatment group, administered with ASMq ethanol extract at 400, 800 and 1600 mg/kg body weight, respectively, until the 45th day, continued by normal saline administration for another 45 days. Groups 6–8 were served as the treatment group, administered with normal saline for the first 45 days from the day of DMH injection, ASMq ethanol extract at three different doses to be administered until the end of the second 45th day. All rats were sacrificed at 91st day and the colons were analyzed for aberrant crypt foci (ACF) formation and crypt multiplicity. Results showed that ASMq ethanol extract reduced the number of ACF, AC and crypt multiplicity significantly (P < .05). It suggested that ASMq ethanol extract had chemoprotective effects on DMH-induced colon carcinogenesis, by suppressing the development of preneoplastic lesions, and probably exerted protection against the initiation and promotion steps of colon carcinogenesis.

Effect of gallic acid on xenobiotic metabolizing enzymes in 1,2-dimethyl hydrazine induced colon carcinogenesis in Wistar rats – A chemopreventive approach

Colon cancer risk may be influenced by phase I and II xenobiotic–metabolizing enzyme systems. The chemopreventive agent gallic acid (GA), a plant polyphenol, is found in various natural products. Our aim was to evaluate the potential role of GA on drug-metabolizing enzymes in 1,2-dimethyl hydrazine (DMH) induced rat colon carcinogenesis. The total experimental duration was 30 weeks. The effect of GA (50 mg/kg b.w.) on the activities of phase I enzymes (cytochrome P450 and cytochrome b5) and phase II enzymes (glutathione S-transferase, DT-diaphorase and gamma glutamyl transpeptidase) were assessed in the liver and colonic mucosa and the colons were also examined visually. In DMH induced rats, there was a decrease in the activities of phase II enzymes and an increase in the activities of phase I enzymes. On GA supplementation, there was a significant increase in the activities of phase II enzymes and a significant decrease in the activities of phase I enzymes, in addition to the decreased tumor incidence. Histopathological changes also confirm this. Thus, the marked potential of GA in modulating the phase I and II xenobiotic-metabolizing enzymes suggests that GA may have a major impact on colon cancer chemoprevention.

Dose-dependent effect of oregano (Origanum vulgare L.) on lipid peroxidation and antioxidant status in 1,2-dimethylhydrazine-induced rat colon carcinogenesis

Colon cancer is a major cause of morbidity and mortality in developed and developing countries. Diet and dietary constituents play a major role in the aetiology of colon cancer. We have investigated the effect of an aqueous extract of oregano (Origanum vulgare. L.) on lipid peroxidation and anti-oxidant status in 1,2-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. We aimed to identify the important antioxidants present in Indian oregano using RP-HPLC. DMH (20 mgkg(-1)) was administered subcutaneously once a week for the first four weeks and then discontinued. Oregano was supplemented every day orally at a dose of 20, 40 or 60 mgkg(-1) to different groups of rats for 15 weeks. After this time the rats were killed and the colons were examined visually and evaluated biochemically. The levels of lipid peroxidation products, such as thiobarbituric acid reactive substances and conjugated dienes were significantly higher in the liver whereas in caecum and colon the levels were lower in DMH-treated animals as compared with control rats. The levels of the anti-oxidants superoxide dismutase, catalase, reduced glutathione, glutathione reductase, glutathione peroxidase and glutathione-S-transferase were decreased in DMH-treated rats, but were significantly reversed on oregano supplementation. Oregano supplementation (40 mgkg(-1)) had a modulatory role on tissue lipid peroxidation and antioxidant profile in colon cancer-bearing rats, which suggested a possible anti-cancer property of oregano.

Astaxanthin inhibits tumor invasion by decreasing extracellular matrix production and induces apoptosis in experimental rat colon carcinogenesis by modulating the expressions of ERK-2, NFkB and COX-2

Colon cancer is the third most malignant neoplasm in the world and it remains an important cause of mortality in Asian and Western countries. Astaxanthin (AST), a major component of carotenoids possesses attractive remedial features. The purpose of this study is to investigate the possible mechanism of action of astaxanthin against 1, 2 dimethyl hydrazine (DMH)-induced rat colon carcinogenesis. Wistar male rats were randomized into five groups, group 1 were control rats, group 2 were rats that received AST (15 mg/kg body wt p.o. everyday), rats in group 3 were induced with DMH (40 mg/kg body wt, s.c.), DMH-induced rats in groups 4 and 5 were either pre or post initiated with AST, respectively as in group 2. DMH-induced rats exhibited elevated expressions of Nuclear factor kappa B-p65 (NF-κB-p65), Cyclooxygenase-2 (COX-2), Matrixmetallo proteinases (MMP) 2/9, Proliferating cell nuclear antigen (PCNA), and Extracellular signal-regulated kinase-2 (ERK-2) as confirmed by immunofluorescence. Further, Westernblot analysis of MMPs-2/9, ERK-2 and Protein kinase B (Akt) revealed increased expressions of these proteins in DMH-induced groups of rats. AST-treatment decreased the expressions of all these vital proteins, involved in colon carcinogenesis. The ability of AST to induce apoptosis in the colon of DMH-induced rats was confirmed by Annexin-V/PI staining in a confocal microscopy, DNA fragmentation analysis and expression of caspase-3 by Western blotting. In conclusion, astaxanthin exhibits anti-inflammatory and anti-cancer effects by inducing apoptosis in DMH-induced rat colon carcinogenesis by modulating the expressions of NFkB, COX-2, MMPs-2/9, Akt and ERK-2.