Chemopreventive effect of artesunate in 1,2-dimethylhydrazine-induced rat colon carcinogenesis.
ABSTRACT: Artesunate (ART) is a semisynthetic derivative of artemisinin. Artemisinin and its derivatives have shown profound cytotoxicity and antitumor activity in addition to antimalarial activity in various studies. As the in vivo chemopreventive efficacy of ART in colon carcinogenesis has not been investigated so far, the aim of the current study was to study the chemopreventive effect of ART in 1,2-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. Animals were divided into four groups (n = 6): Group I - vehicle (1 mM ethylenediaminetetraacetic acid), Group II - DMH (20 mg/kg), Group III - DMH + 5-fluorouracil (81 mg/kg), Group IV - DMH + ART (6.7 mg/kg). After completion of 15 weeks of treatment, rats were sacrificed under ether anesthesia by cervical dislocation for assessment of lipid peroxidation (LPO), antioxidant status, average number of aberrant crypt foci (ACF), and cytokine levels. ART administration significantly decreased the average number of ACF/microscopic field. Similarly, LPO level was decreased and antioxidant activities were enhanced after ART treatment. ART decreased the levels of proinflammatory cytokines and induced apoptosis in the colons of DMH-treated rats. The results of this study suggest that ART has a beneficial effect against chemically induced colonic preneoplastic progression in rats.
Project description:Cancer as a multistage process can be reversed or blocked by using chemopreventive agents. Colon cancer chemoprevention has been widely investigated using cyclooxygenase inhibitors and many other chemicals of synthetic or natural origin. This particular study was carried out to assess the colon cancer chemopreventive effect of hydro-methanol extract of Rumex abyssinicus rhizome on rats.Colon cancer chemopreventive potential of hydro-methanol extract of Rumex abyssinicus rhizome was determined based on the number and multiplicity of aberrant crypt foci (ACF). Fifteen DMH (1, 2-dimethylhydrazine) treated and five untreated Wistar female rats were used. DMH was administered subcutaneously 30 mg/kg, after its pH was adjusted to 6.5-7. Treatment groups started receiving extract after six weeks of weekly DMH injections. The rats were divided in to four groups: Group 1 received only oral normal saline, Group 2 received DMH and normal saline, Group 3 and 4 received DMH plus 250 mg/kg and 500 mg/kg extract, respectively. Specific phytoconstituents of the plant, which were reviewed from original articles, were virtually evaluated for cyclooxygenase-2 (COX-2) inhibition. The binding energies and interactions of the phytochemicals from Rumex abyssinicus against COX-2 were determined by Autodock4.2.There was a statistically significant reduction (p-value < 0.05) in the number of aberrant crypt (AC) and aberrant crypt foci (ACF) at both administered doses. However, significant association (p-value > 0.05) was not observed in reducing crypt multiplicity. The docking process resulted in estimated binding energies [-6.83 kcal/mol to -7.9 kcal/mol] which are closer to the positive controls or Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) [-4.55 kcal/mol to -10.84 kcal/mol]. The phytochemical-COX-2 interaction indicated the involvement of key amino acid residues in inhibition of cyclooxygenase like ARG120, TYR355, TYR385, SER530 and GLY526.Rumex abyssinicus had demonstrated a chemopreventive potential at post-initiation stage. As the virtual screening data suggested, COX-2 inhibition by the anthraquinones in the extract could be one mechanism for the observed chemopreventive effect.
Project description:Djulis is a functional grain containing prebiotic dietary fiber, which has an anti-cancer potential. This study examined the preventive effect of djulis alone or in combination with Lactobacillus acidophilus on colon carcinogenesis induced by 1,2-dimethylhydrazine (DMH) and dextran sulfate sodium (DSS). Rats were divided into five groups and fed B (AIN-93G, blank), C (AIN-93G, control), D (10% djulis), DLA (10% djulis plus 5 × 106 cfu L. acidophilus/g), and DHA (10% djulis plus 5 × 107 cfu L. acidophilus/g) diets, respectively. All rats except for those in group B received three doses of DMH (40 mg/kg) by intraperitoneal injection and 3% DSS in drinking water. After 10 weeks of feeding, the colon was analyzed for precancerous lesions and biomarkers. DMH and DSS treatment induced aberrant crypt foci (ACF), especially in the distal colon. D, DLA, and DHA significantly reduced the numbers of total ACF, sialomucin-producing ACF (SIM-ACF), and mucin-depleted foci (MDF) in the distal colon compared to C. Additionally, DLA and DHA further downregulated the expressions of proliferating cell nuclear antigen (PCNA) and cyclooxygenase-2 (COX-2) and regulated apoptosis-related proteins. These results suggest that synbiotic combination of djulis and L. acidophilus shows the best inhibitory effect on colon carcinogenesis via regulation of proliferative, inflammatory, and apoptotic pathways.
Project description:The toxicity of dietary E 171, a food grade titanium dioxide was evaluated. A recent study reported rats receiving E 171 in water developed inflammation and aberrant crypt foci (ACF) in the gastrointestinal tract. Here, rats received food containing E 171 (7 or 100 days). The 100-day study included feeding E 171 after dimethylhydrazine (DMH) or vehicle only pretreatment. Food consumption was similar between treatment groups with maximum total cumulative E 171 exposure being 2617?mg/kg in 7 days and 29,400?mg/kg in 100 days. No differences were observed due to E 171 in the percentage of dendritic, CD4+ T or Treg cells within Peyer's patches or the periphery, or in cytokine production in plasma, sections of jejunum, and colon in 7- or 100-day E 171 alone fed rats. Differences were observed for IL-17A in colon (400 ppm E 171 + DMH) and IL-12p70 in plasma (40 ppm E 171 + DMH). E 171 had no effect on histopathologic evaluations of small and large intestines, liver, spleen, lungs, or testes, and no effects on ACF, goblet cell numbers, or colonic gland length. Dietary E 171 administration (7- or 100-day), even at high doses, produced no effect on the immune parameters or tissue morphology.
Project description:Vitamin D3 and metformin are widely used in humans for regulating mineral metabolism and as an antidiabetic drug, respectively; and both of them have been shown to have chemopreventive effects against various tumors. This study was designed to investigate the potential synergistic chemopreventive effects of vitamin D3 and metformin against the development of early colon neoplasia in two models. The first model was a 1,2-dimethylhydrazine dihydrochloride (DMH)-induced colon cancer rat model and the second, a DMH-dextran sodium sulfate (DSS)-induced colitis-associated colon neoplasia mouse model. Compared with either vitamin D3 or metformin alone, combined use of vitamin D3 and metformin showed more pronounced effect in reducing the numbers of aberrant crypt foci (ACF) and tumor in the colon. The most prominent inhibitory effects were observed in the vitamin D3 medium dose (100 IU/kg/d) and metformin medium dose (120 mg/kg/d) combination group. Furthermore, our results showed that enhancement of metformin's chemopreventive effects by vitamin D3 was associated with downregulation of S6P expression, via the AMPK (IGFI)/mTOR pathway. In addition, enhancement of vitamin D3's chemopreventive effects by metformin was associated with inhibition of the protein expressions of c-Myc and Cyclin D1, via the vitamin D receptor/?-catenin pathway. These findings show that the combined use of vitamin D3 and metformin exhibits synergistic effects against the development of early colon neoplasia. They suggest that the combined use of vitamin D3 and metformin may represent a novel strategy for chemoprevention of colorectal cancer.
Project description:BACKGROUND: Acanthus ilicifolius, a mangrove medicinal plant, is traditionally used to treat a variety of diseases. The aim of this research is to assess the chemoprotective outcomes of A. ilicifolius ethanolic extract against azoxymethane (AOM) induced colonic aberrant crypt foci (ACF) in rats. METHODOLOGY/PRINCIPAL FINDINGS: In our study, rats were arranged in to five groups. Rats in the normal control group were given subcutaneous injections of normal saline once weekly for 2 weeks. The AOM control, reference and treatment groups were given subcutaneous injection of AOM, 15 mg/kg body weight, once weekly for 2 weeks each. The reference group was treated with 35 mg/kg 5-Fluorouracil via intraperitoneal injection once weekly for 8 weeks, and the treatment groups were administered by gavage with 250 and 500 mg/kg A. ilicifolius extract daily for 8 weeks. Both normal and AOM control groups received the vehicle; 10% Tween-20 only. Rats treated with 250 mg/kg and 500 mg/kg of A. ilicifolius extracts showed a decrease in the mean number of ACF by 65% and 53%, respectively. Those fed with A. ilicifolius showed significantly decreased multiplicity of ACF formations when compared with the results from the AOM control group. The 250 mg/kg A. ilicifolius treatment group showed significant decreases in lipid peroxidation MDA levels when compared with the AOM control group. In immunohistochemistry staining, the proliferating nuclear cell antigen (PCNA)-positive cells were significantly higher in the AOM control group than in the A. ilicifolius-treated groups. RT-PCR showed that A. ilicifolius caused a change in the regulation of apoptosis-related genes expression. CONCLUSION/SIGNIFICANCE: The results of the current study show that AOM-treated rats receiving oral exposure to A. ilicifolius demonstrated a significant decrease in the number of ACF in the colon when compared to AOM-treated rats receiving vehicle only. A ilicifolius may be an effective herbal approach for the prevention of AOM-induced ACF in the rat colon.
Project description:Schiff-based complexes as a source of cancer chemotherapeutic compounds have been subjected to the variety of anticancer studies. The in-vitro analysis confirmed the CdCl2(C14H21N3O2) complex possess cytotoxicity and apoptosis induction properties in colon cancer cells, so lead to investigate the inhibitory efficiency of the compound on colonic aberrant crypt foci (ACF). Five groups of adult male rats were used in this study: Vehicle, cancer control, positive control groups and the groups treated with 25 and 50?mg/kg of complex for 10 weeks. The rats in vehicle group were injected subcutaneously with 15?mg/kg of sterile normal saline once a week for 2 weeks and orally administered with 5% Tween-20 (5?ml/kg) for 10 weeks, other groups were injected subcutaneously with 15?mg/kg azoxymethane once a week for 2 weeks. The rats in positive groups were injected intra-peritoneally with 35?mg/kg 5-Flourouracil four times in a month. Administration of the complex suppressed total colonic ACF formation up to 73.4% (P?<?0.05). The results also showed that treatment with the complex significantly reduced the level of malondialdehyde while increasing superoxide dismutase and catalase activities. Furthermore, the down-regulation of PCNA and Bcl2 and the up-regulation of Bax was confirmed by immunohistochemical staining.
Project description:Colorectal cancer (CRC) is a cancer associated with chronic inflammation. Whole grains and probiotics play a protective role against CRC. Fermented grains are receiving increased attention due to their anti-inflammatory and anti-cancer activities. Our previous study found that a combination of germinated brown rice (GBR) with probiotics suppressed colorectal carcinogenesis in rats. However, the cancer-preventive effect of probiotic-fermented GBR has not been reported. This study investigated the preventive effect and possible mechanism of GBR fermented by Lactobacillus acidophilus (FGBR) on colorectal carcinogenesis in rats induced by 1,2-dimethylhydrazine (DMH) and dextran sulfate sodium (DSS). DMH/DSS treatment induced preneoplastic aberrant crypt foci (ACF), elevated serum levels of tumor necrosis factor (TNF)-?, interleukin (IL)-6 and IL-1?, as well as decreased pro-apoptotic Bax expression. GBR and FGBR reduced the primary ACF number and decreased TNF-?, IL-6 and IL-1? levels. GBR and FGBR at the 2.5% level increased pro-apoptotic cleaved caspase-3 and decreased anti-apoptotic B-cell lymphoma 2 (Bcl-2) expressions. FGBR at the 2.5% level further reduced the number of sialomucin-producing ACF (SIM-ACF) and increased Bax expression. These results suggest that FGBR may inhibit preneoplastic lesions of the colon via activating the apoptotic pathway. This fermented rice product may have the potential to be developed as a novel dietary supplement for CRC chemoprevention.
Project description:Annona muricata has been used in folk medicine for the treatment of cancer and tumors. This study evaluated the chemopreventive properties of an ethyl acetate extract of A. muricata leaves (EEAML) on azoxymethane-induced colonic aberrant crypt foci (ACF) in rats. Moreover, the cytotoxic compound of EEAML (Annomuricin E) was isolated, and its apoptosis-inducing effect was investigated against HT-29 colon cancer cell line using a bioassay-guided approach. This experiment was performed on five groups of rats: negative control, cancer control, EEAML (250 mg/kg), EEAML (500 mg/kg) and positive control (5-fluorouracil). Methylene blue staining of colorectal specimens showed that application of EEAML at both doses significantly reduced the colonic ACF formation compared with the cancer control group. Immunohistochemistry analysis showed the down-regulation of PCNA and Bcl-2 proteins and the up-regulation of Bax protein after administration of EEAML compared with the cancer control group. In addition, an increase in the levels of enzymatic antioxidants and a decrease in the malondialdehyde level of the colon tissue homogenates were observed, suggesting the suppression of lipid peroxidation. Annomuricin E inhibited the growth of HT-29 cells with an IC50 value of 1.62 ± 0.24 ?g/ml after 48 h. The cytotoxic effect of annomuricin E was further substantiated by G1 cell cycle arrest and early apoptosis induction in HT-29 cells. Annomuricin E triggered mitochondria-initiated events, including the dissipation of the mitochondrial membrane potential and the leakage of cytochrome c from the mitochondria. Prior to these events, annomuricin E activated caspase 3/7 and caspase 9. Upstream, annomuricin E induced a time-dependent upregulation of Bax and downregulation of Bcl-2 at the mRNA and protein levels. In conclusion, these findings substantiate the usage of A. muricata leaves in ethnomedicine against cancer and highlight annomuricin E as one of the contributing compounds in the anticancer activity of A. muricata leaves.
Project description:Ku-jin tea (KJT) is a health beverage prepared from the leaves of the plant Acer tataricum subsp. ginnala that has been consumed in some regions of China for thousands of years. KJT contains high levels of anti-inflammatory and antioxidative compounds such as ginnalins, but little is known about the chemopreventive effect of KJT on colon cancer. In this study, we investigated the preventive effects of KJT on colon carcinogenesis using the azoxymethane (AOM)-induced precancerous colorectal lesion model in rats. The results showed that the number of aberrant crypts, aberrant crypt foci (ACF) and crypts/focus in rats of the KJT?+?AOM group were significantly decreased compared with rats of the AOM group (p?<?0.01). Further exploration of the prevention mechanism of KJT by UPLC-QTOF/MS-based urinary metabolomics showed that 5 metabolic pathways were modulated, including purine metabolism and amino acid metabolism, in the group with KJT. In addition, the levels of the immunomodulatory cytokines IL-1? and IL-10 were significantly decreased, and the levels of IL-2 in the serum of AOM rats increased after KJT treatment. Our present data suggest that KJT can inhibit AOM-induced colonic ACF formation and might be a useful chemopreventive agent against colorectal carcinogenesis.
Project description:Tumor suppressor p53 plays a major role in colorectal cancer development. The present study explores the effects of p53-modulating agent CP-31398 alone and combined with celecoxib on azoxymethane-induced aberrant crypt foci (ACF) and colon adenocarcinomas in F344 rats. Maximum tolerated doses were 400 and 3,000 ppm for CP-31398 and celecoxib, respectively. ACF and tumor efficacy endpoints were carried out on azoxymethane-treated 7-week-old rats (48 per group) fed the control AIN-76A diet. Two weeks after carcinogen treatment, rats were fed the diets containing 0, 150, or 300 ppm CP-31398, 300 ppm celecoxib, or 150 ppm CP-31398 plus 300 ppm celecoxib. ACF and colon adenocarcinomas were determined at 8 and 48 weeks after azoxymethane treatment, respectively. Dietary CP-31398 was shown to suppress mean colonic total ACF by 43% and multicrypt ACF by 63%; dietary CP-31398 at 150 and 300 ppm suppressed adenocarcinoma incidence by 30.4% (P < 0.02) and 44% (P < 0.005), respectively, and adenocarcinoma multiplicity by 51% (P < 0.005) and 65% (P < 0.0001), respectively. Dietary celecoxib suppressed colon adenocarcinoma incidence (60%; P < 0.0003) and multiplicity (70%; P < 0.0001). Importantly, combination of low-dose CP-31398 and celecoxib suppressed colon adenocarcinoma incidence by 78% and multiplicity by 90%. Rats that were fed the high-dose CP-31398 or a combination of low-dose CP-31398 and celecoxib showed considerable enhancement of p53 and p21(WAF1/CIP) expression, apoptosis, and reduced tumor cell proliferation in colonic tumors. These observations show, for the first time, that CP-31398 possesses significant dose-dependent chemopreventive activity in a well-established colon cancer model and that a combination of low-dose CP-31398 and celecoxib significantly enhanced colon cancer chemopreventive efficacy.