Anticarcinogenic activity of methanol extract of Melastoma malabathricum leaves is attributed to the presence of phenolics compounds and the activation of endogenous antioxidant system

Melastoma malabathricum (M. malabathricum) extracts have been reported to exert various pharmacological activities including antioxidants, anti-inflammatory and antiproliferative activities. The objective of the present study was to determine the anticarcinogenic activity of its methanol extract (MEMM) against the azoxymethane (AOM)-induced early colon carcinogenesis in rats. Rats were randomly assigned to five groups (n=6) namely normal control, negative control, and treatment (50, 250 or 500 mg/kg of MEMM) groups. Colon tissues were harvested for histopathological analysis and endogenous antioxidant system determination. MEMM was also subjected to HPLC analysis. Findings showed that MEMM significantly (p<0.05) reversed the AOM-induced carcinogenicity by: i) reducing the formation of aberrant crypt foci (ACF) in colon tissues, and; ii) enhancing the endogenous antioxidant activity (catalase, superoxide dismutase and glutathione peroxidase). Moreover, various phenolics has been identified in MEMM. In conclusion, MEMM exerts the in vivo anticarcinogenic activity via the activation of endogenous antioxidant system and synergistic action of phenolics.

Is Sunflower Cooking Oil Desirable for Colorectal Cancer? In Vivo Studies on Azoxymethane-Induced Colon Cancer in Rats

Background: The incorporation of oils in the diet may have promoting or inhibitory effects on Colorectal Cancer (CRC). In this study, azoxymethane (AOM) was used to mimic CRC in rats and the effect of sunflower oil on cancer progression in the colon of the rats was tested. Objective: This study was conducted to investigate the effect of sunflower oil on preneoplastic cancer properties on the colonic mucosal surface for tumors and the aberrant crypt foci (ACF). Methods: Six weeks old Sprague-Dawley male rats were randomized into 4 groups of 6 rats each, namely naïve, positive control, negative control and sunflower oil-fed. CRC was induced by AOM by subcutaneous injection of 20 mg/kg. After CRC induction, the rats were given respective treatment of either basal diet (naïve group), 10 mg/kg indomethacin (positive control), 0.9% saline (negative control), and 7% sunflower oil (experimental group) daily by oral gavage for 42 days. Rats were sacrificed by cervical dislocation; colon samples were visually observed for any tumors on the colonic mucosal surface and evaluated for ACF; histopathological examinations were also performed. Results: The mean body weights of the rats were similar in all groups as per one-way ANOVA. A total of 3 ACF were found in the negative group while none were observed in others. The crypts appeared regular with circular luminal openings and were arranged closely packed together in the naïve group. Crypts in the positive and treated group had a similar appearance like naïve group. Conclusion: Sunflower oil inhibition of the preneoplastic cancer ACF properties were tested but were found to be insignificant when administered during CRC treatment or management. However long-term experiment with a greater number of days will yield better development of tumor and ACF development and will be useful identifying the molecular mechanism.

Selenium and the 15kDa Selenoprotein Impact Colorectal Tumorigenesis by Modulating Intestinal Barrier Integrity

Selenoproteins play important roles in many cellular functions and biochemical pathways in mammals. Our previous study showed that the deficiency of the 15 kDa selenoprotein (Selenof) significantly reduced the formation of aberrant crypt foci (ACF) in a mouse model of azoxymethane (AOM)-induced colon carcinogenesis. The objective of this study was to examine the effects of Selenof on inflammatory tumorigenesis, and whether dietary selenium modified these effects. For 20 weeks post-weaning, Selenof-knockout (KO) mice and littermate controls were fed diets that were either deficient, adequate or high in sodium selenite. Colon tumors were induced with AOM and dextran sulfate sodium. Surprisingly, KO mice had drastically fewer ACF but developed a similar number of tumors as their littermate controls. Expression of genes important in inflammatory colorectal cancer and those relevant to epithelial barrier function was assessed, in addition to structural differences via tissue histology. Our findings point to Selenof’s potential role in intestinal barrier integrity and structural changes in glandular and mucin-producing goblet cells in the mucosa and submucosa, which may determine the type of tumor developing.

Effects of Scrophularia Oxysepala Methanolic Extract on Early Stages of Dimethylhydrazine-Induced Colon Carcinoma in Rats: Apoptosis Pathway Approach

Purpose: Colorectal cancer is one of the most prevalent cancers, worlwide. The present study aimed to examine the effects of Scrophularia Oxysepala (SO) methanolic extract on 1,2-dimethylhydrazine (DMH) induced colon cancer model in the Wistar rats. Methods: The animals administered DMH (40 mg/kg/S.C.) biweekly for two weeks to induce aberrant crypt foci (ACF). Other groups of animals were given the SO extract (50, 100 and 200 mg/kg/orally once/day) either before or after the DMH treatments. In the end, all animals were killed and at necropsy, the colon samples examined. The ACF, Aberrant crypt (AC), crypt multiplicity (CM), caspase 3 protein and apoptosis measurement were performed. Results: The SO extract significantly (P<0.001) decreased the number of AC, ACF, and CM in all pre and post-treated groups and caused significant increases in Caspase 3 and apoptosis as compared to the DMH group. However, post-treated animals showed significantly more effective than pre-treatment groups. Methanolic extract of SO showed a chemopreventive potential, by effectively reducing the number of AC, ACF, and CM and increasing caspase 3 protein and apoptosis. Conclusion: One of the possible mechanisms might be involved in the induction of apoptosis through the caspase 3 mediated pathway.

The Use of Natural Fiber-Rich Food Product Is Safe and Reduces Aberrant Crypt Foci in a Pre-Clinical Model

Background: Colorectal cancer is a highly prevalent disease, requiring effective strategies for prevention and treatment. The present research aimed to formulate a natural fiber-rich food product (NFRFP) and to evaluate its safety, toxicogenetics, and effects on aberrant crypt foci induced by 1,2-dimethyl-hydrazine in a preclinical model. Methods: A total of 78 male Wistar rats were distributed in six experimental groups: negative control, positive control (1,2-Dimethylhydrazine—40 mg/Kg), and four groups fed with 10% NFRFP: NFRFP, pre-treatment protocol, simultaneous treatment, and post-treatment protocol. Results: The NFRFP was shown to be a good source of fibers and did not change biometric, biochemical, hematological, and inflammatory parameters, and did not induce signs of toxicity and genotoxicity/carcinogenicity. NFRFP exhibited a chemopreventive effect, in all protocols, with damage reduction (% DR) of 75% in the comet test. NFRFP reduced the incidence of aberrant crypt outbreaks by 49.36% in the post-treatment protocol. Conclusions: The results suggest the applicability of NFRFP in the human diet due to potential production at an industrial scale and easy technological application in different products, since it could be incorporated in food without altering or causing small changes in final product sensory characteristics.

Enhancement of Anti-Tumoral Immunity by β-Casomorphin-7 Inhibits Cancer Development and Metastasis of Colorectal Cancer

β-Casomorphin-7 (BCM) is a degradation product of β-casein, a milk component, and has been suggested to affect the immune system. However, its effect on mucosal immunity, especially anti-tumor immunity, in cancer-bearing individuals is not clear. We investigated the effects of BCM on lymphocytes using an in vitro system comprising mouse splenocytes, a mouse colorectal carcinogenesis model, and a mouse orthotopic colorectal cancer model. Treatment of mouse splenocytes with BCM in vitro reduced numbers of cluster of differentiation (CD) 20+ B cells, CD4+ T cells, and regulatory T cells (Tregs), and increased CD8+ T cells. Administration of BCM and the CD10 inhibitor thiorphan (TOP) to mice resulted in similar alterations in the lymphocyte subsets in the spleen and intestinal mucosa. BCM was degraded in a concentration- and time-dependent manner by the neutral endopeptidase CD10, and the formed BCM degradation product did not affect the lymphocyte counts. Furthermore, degradation was completely suppressed by TOP. In the azoxymethane mouse colorectal carcinogenesis model, the incidence of aberrant crypt foci, adenoma, and adenocarcinoma was reduced by co-treatment with BCM and TOP. Furthermore, when CT26 mouse colon cancer cells were inoculated into the cecum of syngeneic BALB/c mice and concurrently treated with BCM and TOP, infiltration of CD8+ T cells was promoted, and tumor growth and liver metastasis were suppressed. These results suggest that by suppressing the BCM degradation system, the anti-tumor effect of BCM is enhanced and it can suppress the development and progression of colorectal cancer.

Chemopreventive Effect of Stoechospermum marginatum against Experimental Colon Carcinogenesis Induced by 1, 2-Dimethyl Hydrazine

Background: Colon cancer is the one most prevalent malignancy in the world and its incidence is increasing due to changing life styles, environmental factors, etc. Conventional chemotherapy for cancer is limited due to development of chemoresistance and severe side effects. Natural products have received great attention in the recent years owing to its reduced toxicity and side effects. The present was undertaken to evaluate chemopreventive potential of ethanolic extract of Stoechospermum marginatum in experimentally induced colon carcinogenesis in rats. Methods: Healthy male wistar rats were divided into 6 groups and received following treatments: Vehicle (Group I); S. marginatum extract (Group II), DMH alone (Group III), DMH + 5-Fluorouracil (Group IV), DMH +S. marginatum extract at 100 mg/kg (Group V) and DMH +S. marginatum extract at 200 mg/kg (Group VI). Colon tumour was induced using 1, 2-dimethylhydrazine (DMH). Result: S. marginatum extract ameliorated oxidative damaging effects of DMH. S. marginatum extract increased expression of Bax, caspase 3 and caspase 9; decreased expression of Bcl-2 and restored levels of COX-2 compared to tumor control. Reduced aberrant crypt foci, hyperplastic and inflammatory changes in colon were observed with S. marginatum compared to tumour control. The findings suggest chemopreventive potential of S. marginatum.

Azoxymethane Alters the Plasma Metabolome to a Greater Extent in Mice Fed a High-Fat Diet Compared to an AIN-93 Diet

Consumption of a high-fat diet (HFD) links obesity to colon cancer in humans. Our data show that a HFD (45% energy fat versus 16% energy fat in an AIN-93 diet (AIN)) promotes azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) formation in a mouse cancer model. However, the underlying metabolic basis remains to be determined. In the present study, we hypothesize that AOM treatment results in different plasma metabolomic responses in diet-induced obese mice. An untargeted metabolomic analysis was performed on the plasma samples by gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). We found that 53 of 144 identified metabolites were different between the 4 groups of mice (AIN, AIN + AOM, HFD, HFD + AOM), and sparse partial least-squares discriminant analysis showed a separation between the HFD and HFD + AOM groups but not the AIN and AIN + AOM groups. Moreover, the concentrations of dihydrocholesterol and cholesterol were inversely associated with AOM-induced colonic ACF formation. Functional pathway analyses indicated that diets and AOM-induced colonic ACF modulated five metabolic pathways. Collectively, in addition to differential plasma metabolomic responses, AOM treatment decreases dihydrocholesterol and cholesterol levels and alters the composition of plasma metabolome to a greater extent in mice fed a HFD compared to the AIN.

A Review of Auraptene as an Anticancer Agent

Auraptene is a bioactive monoterpene coumarin isolated from Citrus aurantium and Aegle marmelos that belong to the Rutaceae family. Auraptene can modulate intracellular signaling pathways that control cell growth, inflammation and apoptosis and can exert pharmacological properties such as anti-bacterial, anti-fungal, antileishmania and anti-oxidant activity. Auraptene had inhibitory and chemo-preventive effects on the proliferation, tumorigenesis and growth of several cancer cell lines through increase in the activity of glutathione S-transferase, formation of DNA adducts and reduction of the number of aberrant crypt foci. Auraptene exhibits anticancer effects via targeting different cell signaling pathways such as cytokines, genes modulating cellular proliferation, growth factors, transcription factors and apoptosis. The present review is a detailed survey of scientific researches on the cytotoxicity and anticancer activity of Auraptene on cancer cells and tumor bearing animals.