DMH-induced Colon Carcinogenesis Research Articles

Chemoprevention of DMH Induced Colon Carcinogenesis by Combination Administration of Lactobacillus acidophilus, Calcium and Moringa oleifera Leaves Extract

Colon cancer has become one of the most prevalent and deadliest type of cancer in the globe in recent years. In order to prevent colon cancer triggered by DMH (1,2-dimethyl hydrazine hydrochloride), this study was to investigate the potential chemopreventive effects of calcium citrate, Lactobacillus acidophilus, and Moringa oleifera leaf extract. Sprague Dawley rats were randomized into 10 different groups and received subcutaneous injections of DMH (30 mg/kg) for 8 weeks of duration. Treatment groups were served for 4 weeks, 5-Flurouracil (20 mg/kg) was dosed with two intraperitoneal injections in a week and. L. acidophilus (1 × 109 cfu/kg p.o.), calcium citrate (2 mg/kg p.o.) and hydroalcoholic extract of M. oleifera leaves (100 and 200 mg/kg p.o.) were used for daily. All animals were killed after the completion of treatment, and colonic tissues were assessed for biochemical and histopathological parameters. DMH treatment-induced cellular and systemic oxidative stress results in depletion of cellular antioxidant enzyme levels with an alteration in hematological counts. The colonic tissues had a loose histoarchitecture with severe cellular infiltration, edema in the epithelium, and a moderate nuclear/cytoplasmic ratio, goblet cells. Combination treatments of L. acidophilus (LA), Calcium citrate (CC), and hydroalcoholic extract of M. oleifera leaves (ME) showed positive improvements in antioxidant enzyme levels, hematology count, and colonic tissue histoarchitecture. From outcomes of the present work concluded that a combination treatment of L. acidophilus, calcium citrate and a hydroalcoholic extract of M. oleifera leaves showed chemo-preventive effects against colon cancer triggered by DMH.

Vinpocetine mitigates DMH-induce pre-neoplastic colon damage in rats through inhibition of pro-inflammatory cytokines.

Colorectal cancer (CRC) is currently recognized as the third most prevalent cancer worldwide. Vinpocetine is a synthetic derivative of the vinca alkaloid vincamine. It has been found effective in ameliorating the growth and progression of cancerous cells. However, its pharmacological effect on colon damage remains elusive. Hence, in this study, we have shown the role of vinpocetine in DMH-induced colon carcinogenesis. At first, male albino Wistar rats were administered with DMH consistently for four weeks to induce pre-neoplastic colon damage. Afterward, animals were treated with vinpocetine (4.2 and 8.4mg/kg/day p.o.) for 15days. Serum samples were collected to assess the physiological parameters, including ELISA and NMR metabolomics. Colon from all the groups was collected and processed separately for histopathology and western blot analysis. Vinpocetine attenuated the altered plasma parameters; lipid profile and showed anti-proliferative action as evidenced by suppressed COX-2 stimulation and decreased levels of IL-1β, IL-2, IL-6, and IL-10. Vinpocetine is significantly effective in preventing CRC which may be associated with its anti-inflammatory and antioxidant potential. Accordingly, vinpocetine could serve as a potential anticancer agent for CRC treatment and thus be considered for future clinical and therapeutic research.

Hesperetin and Capecitabine Abate 1,2 Dimethylhydrazine-Induced Colon Carcinogenesis in Wistar Rats via Suppressing Oxidative Stress and Enhancing Antioxidant, Anti-Inflammatory and Apoptotic Actions.

Colon cancer is a major cause of cancer-related death, with significantly increasing rates of incidence worldwide. The current study was designed to evaluate the anti-carcinogenic effects of hesperetin (HES) alone and in combination with capecitabine (CAP) on 1,2 dimethylhydrazine (DMH)-induced colon carcinogenesis in Wistar rats. The rats were given DMH at 20 mg/kg body weight (b.w.)/week for 12 weeks and were orally treated with HES (25 mg/kg b.w.) and/or CAP (200 mg/kg b.w.) every other day for 8 weeks. The DMH-administered rats exhibited colon-mucosal hyperplastic polyps, the formation of new glandular units and cancerous epithelial cells. These histological changes were associated with the significant upregulation of colon Ki67 expression and the elevation of the tumor marker, carcinoembryonic antigen (CEA), in the sera. The treatment of the DMH-administered rats with HES and/or CAP prevented these histological cancerous changes concomitantly with the decrease in colon-Ki67 expression and serum-CEA levels. The results also indicated that the treatments with HES and/or CAP showed a significant reduction in the serum levels of lipid peroxides, an elevation in the serum levels of reduced glutathione, and the enhancement of the activities of colon-tissue superoxide dismutase, glutathione reductase and glutathione-S-transferase. Additionally, the results showed an increase in the mRNA expressions of the anti-inflammatory cytokine, IL-4, as well as the proapoptotic protein, p53, in the colon tissues of the DMH-administered rats treated with HES and/or CAP. The TGF-β1 decreased significantly in the DMH-administered rats and this effect was counteracted by the treatments with HES and/or CAP. Based on these findings, it can be suggested that both HES and CAP, singly or in combination, have the potential to exert chemopreventive effects against DMH-induced colon carcinogenesis via the suppression of oxidative stress, the stimulation of the antioxidant defense system, the attenuation of inflammatory effects, the reduction in cell proliferation and the enhancement of apoptosis.

Effect of maitake mushrooms thick extract on the state of antioxidant system in rats with DMH-induced colon carcinogenesis

Colorectal cancer is a dangerous oncological disease that requires serious complex treatment. This type of oncopathology occurs due to atypical growth of the epithelium of the mucous layer that lines the intestinal walls. Colon cancer is characterized by slow development, so prevention and timely diagnosis are a priority.
 The main advantage of using oncoprotectors based on natural raw materials in clinical practice is their low toxicity and the possibility of long-term use without significant side effects. That is why the development and study of such drugs are relevant.
 The aim of the research was to study indicators of oxidative processes and antioxidant systems in rats with chemically induced colon carcinogenesis against the background of maitake mushrooms thick extract use.
 The study was performed on 120 white male rats weighing 190–210 g. Adenocarcinoma of the colon was modeled by administering 1,2-dimethylhydrazine (DMH) hydrochloride for 30 weeks (1 time per week). A thick extract from maitake mushrooms was administered intragastrically daily at a dose of 150 mg/kg of animal body weight. Blood and liver samples were taken for research monthly. The state of the pro- and antioxidant systems was studied by the content of oxidative modification of proteins products neutral and alkaline character, superoxide dismutase and catalase activity, contents of reduced glutathione and ceruloplasmin.
 It was found that DMH-induced colon carcinogenesis in rats is accompanied by an increase in the activity of free radical oxidation processes. It is evidenced by a decrease in superoxide dismutase activity, catalase activity, a significant reduction in the content of reduced glutathione, an increase in the content of ceruloplasmin and products of oxidative modification of proteins in the blood serum and liver of animals. The effectiveness of maitake mushrooms thick extract and its positive influence on the activity of the studied enzymes and the content of OMP products in investigated tissues was experimentally proved.
 The use of maitake mushrooms thick extract under conditions of DMH-induced colon carcinogenesis in rats led to the normalization of antioxidant protection indicators and a significant decrease in the indicators of oxidative modification of proteins, which testifies to the suppression of oxidative stress in animals with an oncological process.

EFFECT OF DRY EXTRACT FROM REISHI MUSHROOMS ON THE STATE OF ANTIOXIDANT SYSTEM IN RATS WITH DMH-INDUCED COLON CARCINOGENESIS.

The aim: To study pro- and antioxidant systems indicators in rats with chemically induced colon carcinogenesis on the background of the reishi mushrooms dry extract use. Materials and methods: The study was performed on 120 white male rats. Chronic oncogenic intoxication was modeled by administering 1,2-dimethyl¬hydrazine (DMH) hydrochloride for 30 weeks (1 time per week). A dry extract from the reishi mushrooms was administered intragastrically daily at a dose of 100 mg/kg of the animal's body weight. Blood and liver samples were taken for research monthly. The state of the pro- and antioxidant systems was studied by the content of oxidative modification of proteins products, superoxide dismutase and catalase activity, contents of reduced glutathione and ceruloplasmin. Results: An increase in the activity of free radical oxidation processes after DMH-induced colon carcinogenesis in rats is evidenced by a decrease in the super-oxide dismutase activity, catalase activity, content of reduced glutathione, an increase in the content of ceruloplasmin and products of oxidative modification of proteins in the blood serum and liver of animals. The effectiveness of the dry extract of reishi mushrooms and its positive effect on the state of pro- and antioxidant systems was experimentally proved. Conclusions: The use of the dry extract of reishi mushrooms under conditions of DMH-induced colon carcinogenesis in rats led to normalization of the anti¬oxidant protection system state and the reduction of oxidative stress.

The state of pro- and antioxidant systems in rats with DMH-induced colon carcinogenesis on the background of extracorporeal detoxification

Aim: Cancer is one of the leading causes of death in the world. The aim of this research was to study the indices of pro- and antioxidant systems in rats with dimethylhydrazine (DMH)-induced colon carcinogenesis on the background of the enterosorbent AUT-M use. Materials and methods: The study was performed on 70 white male rats weighing 200–250 g. Adenocarcinoma of the colon was simulated by subcutaneous injection of the DMH (Sigma-Aldrich Chemie, Japan) at a dose of 7.2 mg/kg once a week during 7 months. Enterosorbent AUT-M was administered intragastrically daily for 21 days after simulation of carcinogenesis at a dose of 1 ml of suspension per 100 g of animal body weight. The state of the pro- and antioxidant systems was studied by the content of oxidative modification of proteins products (OMP), the activity of superoxide dismutase (SOD), catalase (CAT), contents of ceruloplasmin (CP) and reduced glutathione (GSH). Results: It was found that DMH-induced colon carcinogenesis in rats is accompanied by disorders in the antioxidant defense system and activation of free radical oxidation processes. Enterosorbent AUT-M provides a significant reduction in the content of OMP370 and OMP430 in both blood serum and liver homogenate of rats. Moreover, the use of enterosorbent AUT-M demonstrated a significant increase in the activity of SOD, CAT, content of GSH and a decrease in CP content in investigated tissues. Conclusion: The use of enterosorbent AUT-М demonstrated prominent potential suppression for oxidative stress and positive effect on antioxidant defense system in rats with DMH-induced colon carcinogenesis.

Oxidants and Antioxidants Synergistically Activate Immuno-Responses During Tumorgenesis

The human immune system possesses powerful surveillance functions to find and eliminate tumor cells. Several steps are involved, such as uptake and presentation of tumor antigens by dendritic cells (DCs) in order to activate T cells, trafficking and infiltration of the tumor with T cells and, finally, recognition and killing of tumor cells. Tumor cells release a number of soluble mediators that may disrupt these steps, thereby creating tolerance or immune escape. We previously published data on a rat animal model showing 1, 2-dimethylhydrazine (DMH) to inhibit DCs activation and enhance T regulatory cells (Treg) expression, ultimately inducing colon carcinogenesis. By feeding rats with mustard seeds (MS), the animals’ immune system shifted from a Th2 to a Th1 pattern, Tregs were inhibited and DCs activation enhanced. In the present study, we tried to isolate the functional fractions of MS and, to our surprise, we found that the oxidant and antioxidant fractions of MS showed synergistic effect on the activation of DCs and CD8+ effector T cells. Neither of the fractions alone, however, had any inhibitory effect on DMH-induced colon carcinogenesis. Differently from the antioxidant fraction, the oxidant fraction activated DCs (CD11c+CD80+, CD11c+CD86+), but not the CD8+ effector T cells. By adding Vitamin E, an acknowledged antioxidant, the oxidant fraction then became able to activate both spleenic DCs and effector T cells (CD8+CD28+). Taken together, these data suggest that the MS oxidant fraction might play an important role in activation of DCs, while also showing that oxidative signals may induce depletion of effector T cells. Addition of the antioxidant MS fraction, or Vitamin E, might restore the survival of effector T cells and eventually help eradicate tumor cells. Thus, MS oxidants, which normally are regarded as having negative effects, may actually function synergistically with antioxidants to prevent chemical-induced carcinogenesis. Keywords: Oxidants; Antioxidants; Immuno-responses; Mustard seeds; Colorectal cancer; Chemoprevention; T cells; Dendritic cells Abbreviations: AITC: Allyl Isothiocyanate; APCs: Antigen-Presenting Cells; CTLs: Cytotoxic T Lymphocytes; DCs: Dendritic Cells; DMH: 1, 2-Dimethylhydrazine; EGCG: Epigallocatechin Gallate; LPO: Lipid Peroxides ; MDA: Malondialdehyde; MHC: Major Histocompatibility Complex; MS: Mustard Seeds; MSE1: Ether Extract of Mustard Seeds; MSE2: Ethanolic Extract of Mustard Seeds; PBS: Phosphate-Buffered Saline; RBC: Red Blood Cell; ROS: Reactive Oxygen Species; TCRs: T Cell Receptors; Treg : T Regulatory Cells; VitE : Vitamin E

Dietary PlsEtn Ameliorates Colon Mucosa Inflammatory Stress and ACF in DMH-Induced Colon Carcinogenesis Mice: Protective Role of Vinyl Ether Linkage.

Ethanolamine plasmalogen (PlsEtn), a sub-class of ethanolamine glycerophospholipids (EtnGpl), is a universal phospholipid in mammalian membranes. Several researchers are interested in the relationship between colon carcinogenesis and colon PlsEtn levels. Here, we evaluated the functional role of dietary purified EtnGpl from the ascidian muscle (87.3 mol% PlsEtn in EtnGpl) and porcine liver (7.2 mol% PlsEtn in EtnGpl) in 1,2-dimethylhydrazine (DMH)-induced aberrant crypt foci (ACF) in vivo, and elucidated the possible underlying mechanisms behind it. Dietary EtnGpl-suppressed DMH-induced aberrant crypt with one foci (AC1) and total ACF formation (P < 0.05). ACF suppression by dietary ascidian muscle EtnGpl was higher compared with dietary porcine liver EtnGpl. Additionally, dietary EtnGpl decreased DMH-induced oxidative damage, overproduction of TNF-α, and expression of apoptosis-related proteins in the colon mucosa. The effect of dietary ascidian muscle EtnGpl showed superiority compared with dietary porcine liver EtnGpl. Our results demonstrate the mechanisms by which dietary PlsEtn suppress ACF formation and apoptosis. Dietary PlsEtn attained this suppression by reducing colon inflammation and oxidative stress hence a reduction in DMH-induced intestinal impairment. These findings provide new insights about the functional role of dietary PlsEtn during colon carcinogenesis.

Brucine Prevents DMH Induced Colon Carcinogenesis in Wistar Rats

Brucine Prevents DMH Induced Colon Carcinogenesis in Wistar Rats

Biochemical and molecular aspects of 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis: a review.

1,2-dimethylhydrazine (DMH) is a member in the class of hydrazines, strong DNA alkylating agent, naturally present in cycads. DMH is widely used as a carcinogen to induce colon cancer in animal models. Exploration of DMH-induced colon carcinogenesis in rodent models provides the knowledge to perceive the biochemical, molecular, and histological mechanisms of different stages of colon carcinogenesis. The procarcinogen DMH, after a series of metabolic reactions, finally reaches the colon, there produces the ultimate carcinogen and reactive oxygen species (ROS), which further alkylate the DNA and initiate the development of colon carcinogenesis. The preneolpastic lesions and histopathological observations of DMH-induced colon tumors may provide typical understanding about the disease in rodents and humans. In addition, this review discusses about the action of biotransformation and antioxidant enzymes involved in DMH intoxication. This understanding is essential to accurately identify and interpret alterations that occur in the colonic mucosa when evaluating natural or pharmacological compounds in DMH-induced animal colon carcinogenesis.

Quercetin attenuated oxidative DNA damage through NRF2 signaling pathway in rats with DMH induced colon carcinogenesis

Accumulating recent studies have demonstrated the preventive and therapeutic effects of polyphonic compounds such as quercetin in colorectal cancer. Therefore, we aimed to evaluate the underlying mechanisms for positive effects of quercetin in rats with 1,2-dimethylhydrazine (DMH)- induced colorectal cancer. For this purpose, male Wistar rats were classified as 6 groups, including group 1 without any intervention, group 2 as quercetin received rats (50 mg/kg), groups 3 as DMH received rats (20 mg/kg) group 4–6 DMH and quercetin received rats. DNA damage, DNA repair, the expression levels and activities of enzymic antioxidants, non-enzymic antioxidants, and NRF2/Keap1 signaling were evaluated in colon tissues of all groups. Our results showed significant suppression of DNA damage and induction of DNA repair in DMH + Quercetin groups, particularly in entire-period in comparison to other groups (p < .05). The expression levels and activities of enzymic and non-enzymic antioxidants were increased in DMH + Quercetin groups (p < .05). Lipid and protein peroxidation were significantly suppressed in DMH + Quercetin groups (p < .05). In addition, quercetin also modulated NRF2/Keap1 signaling and its targets, detoxifying enzymes in DMH + Quercetin groups. Our finding demonstrated that quercetin supplementation effectively reversed DMH-mediated oxidative stress and DNA damage through targeting NRF2/Keap1 signaling pathway.

Transcutaneous Vagus Nerve Stimulation Regulates the Cholinergic Anti-inflammatory Pathway to Counteract 1, 2-Dimethylhydrazine Induced Colon Carcinogenesis in Albino wistar Rats.

The present work was undertaken to study the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on 1, 2-dimethyhydrazine (DMH) induced colon cancer and role of the cholinergic anti-inflammatory pathways (CAP) in the same. Groups of rats were randomly divided into ten groups (n = 8). DMH administration was very well apparent for autonomic dysfunction as observed through distorted hemodynamic (electrocardiogram and heart rate variability), increased aberrant crypt foci and flat neoplastic lesions (methylene blue staining, scanning electron microscopy and Hematoxylin and eosin staining). DMH administration was also recorded for per-oxidative damage. taVNS application restored the autonomic function, cellular morphology and curtailed the oxidative damage. DMH application conspicuously inhibited the mitochondrial apoptosis which was restored back after taVNS application, when scrutinized through immunoblotting and quantitative real time polymerase chain reaction studies. taVNS application up-regulated the CAP as perceived through increased expression for α7 nicotinic acetylcholine receptor(α7nAchR) and decreased expression for nuclear factor kappa-ligand-chain-enhancer of activated B cells (NFκBp65), tissue necrosis factor-α and high mobility group box-1 at protein and mRNA levels. All in all, taVNS up-surged the CAP to counteract DMH induced colon carcinogenesis. Among all the stimulation parameters used, taVNS 3 (pulse width-1 ms, frequency-6 Hz, voltage-6 v, duration-240 min) was observed to be the most effective. Since only chemotherapy and surgery are available options for management of CRC, which are troublesome and painful, there is currently no non-invasive method available for management of CRC. Results of the current study affirmed the effectiveness of taVNS against DMH induced colon cancer. The present study established taVNS as a novel and non-invasive approach toward the management of CRC.

Anti-inflammatory and anticancer effects of p-methoxycinnamic acid, an active phenylpropanoid, against 1,2-dimethylhydrazine-induced rat colon carcinogenesis.

p-methoxycinnamic acid (p-MCA) is an active phenolic acid found in rice bran, turmeric, brown rice, Kaempferia galanga, buckwheat inflorescence, etc. Earlier, we have reported that p-methoxycinnamic acid possesses antioxidant and antilipidperoxidative effects on 1,2-dimethylhyrdrazine (DMH)-induced colon carcinogenesis. The purpose of this study is to unravel the anti-inflammatory and anticancer properties of p-MCA against DMH-induced colon carcinogenesis. Male albino Wistar rats were randomly divided into six groups. Group 1 served as control, group 2 rats received 40mg/kg b.wt. of p-MCA in 0.1% carboxymethylcellulose (CMC) every day, and colon cancer was induced in groups 3-6 using DMH at the dose of (20mg/kg b.wt. subcutaneously) once a week for 15 weeks. In addition, along with DMH, groups 4 (initiation), 5 (post initiation) and 6 (entire period) rats received p-MCA (40mg/kg b.wt.) p.o. every day during different time periods for the total experimental period of 30weeks. Colon of animals treated with DMH showed an increased number of aberrant crypt foci (ACFs), increased nuclear translocation of transcription factor NF-κB p65 subunit, increased expression of inflammatory markers (iNOS, COX-2), cytokines (tumour necrosis factor-α, interleukin-6), cyclin D1, antiapoptotic protein (Bcl-2), metastasis marker (matrix metalloproteinase-2 (MMP-2)) and angiogenic marker (vascular endothelial growth factor VEGF) and decreased expression of pro-apoptotic proteins (Bax, caspases 3 and 9). On supplementing with p-MCA (40mg/kg b.wt.) throughout the entire experimental period, DMH-induced pathological alterations reversed significantly to normal.

Immuno-therapeutic potential of Schistosoma mansoni and Trichinella spiralis antigens in a murine model of colon cancer.

Considerable evidence indicates a negative correlation between the prevalence of some parasitic infections and cancer and their interference with tumor growth. Therefore, parasitic antigens seem to be promising candidates for cancer immunotherapy. In this study, the therapeutic efficacy of autoclaved Schistosoma mansoni and Trichinella spiralis antigens against a colon cancer murine model was investigated. Both antigens showed immunomodulatory potential, as evidenced by a significant decrease in serum IL-17, a significant increase in serum IL-10, and the percentage of splenic CD4+T-cells and intestinal FoxP3+ Treg cells. However, treatment with S. mansoni antigen yielded protection against the deleterious effect of DMH-induced colon carcinogenesis only, with a significant decrease in the average lesion size and number of neoplasias per mouse. For the first time, we report an inhibitory effect of S. mansoni antigen on the progression of chemically induced colon carcinogenesis, but the exact mechanism has yet to be clarified. This anti-tumor strategy could introduce a new era of medicine in which a generation of anticancer vaccines of parasitic origin would boost the therapy for incurable cancers.

Effect of Spirogyra neglecta on the early stages of 1, 2-dimethylhydrazine-induced colon carcinogenesis in rats.

This study focused on the chemopreventive effects of Spirogyra neglecta extract (SNE) and dried S. neglecta mixed diet on the early stages of 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rats. Male Wistar rats were injected with DMH to initiate aberrant crypt foci (ACF) formation. In the initiation stage, SNE significantly decreased the number of ACF in the colon of DMH-treated rats. Rats that received a low dose of SNE showed enhanced activity of several detoxifying and antioxidant enzymes. In the postinitiation stage, a low dose of SNE significantly decreased the number of ACF in the colon of DMH-treated rats. It significantly reduced the number of proliferating cell nuclear antigen-positive cells and increased the number of apoptotic cells in colonic crypts. S. neglecta thus inhibited the development of the early stages of DMH-induced colon carcinogenesis in rats by modulation of xenobiotic metabolizing enzymes and inhibition of cell proliferation as well as induction of apoptosis.

Chemoprevention by Probiotics During 1,2-Dimethylhydrazine-Induced Colon Carcinogenesis in Rats.

Probiotics are believed to have properties that lower the risk of colon cancer. However, the mechanisms by which they exert their beneficial effects are relatively unknown. To assess the impact of probiotics in preventing induction of colon carcinogenesis in rats. The rats were divided into six groups viz., normal control, Lactobacillus plantarum (AdF10)-treated, Lactobacillus rhamnosus GG (LGG)-treated, 1,2-dimethylhydrazine (DMH)-treated, L. plantarum (AdF10)+DMH-treated and L. rhamnosus GG (LGG)+DMH-treated. Both the probiotics were supplemented daily at a dose of 2×1010 cells per day. DMH at a dose of 30mg/kg body weight was administered subcutaneously twice a week for the first 4weeks and then once every week for a duration of 16weeks. Glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and catalase as protein expression of genes involved in apoptosis were assessed during DMH-induced colon carcinogenesis in rats. DMH treatment decreased the activity of GSH, GPx, GST, SOD and catalase. However, AdF10 and LGG supplementation to DMH-treated rats significantly increased the activity of these enzymes. Further, DMH treatment revealed alterations in the protein expressions of various genes involved in the p53-mediated apoptotic pathway such as p53, p21, Bcl-2, Bax, caspase-9 and caspase-3, which, however, were shifted towards normal control levels upon simultaneous supplementation with probiotics. The present study suggests that probiotics can provide protection against oxidative stress and apoptotic-related protein disregulation during experimentally induced colon carcinogenesis.

Transplantation of placenta-derived multipotent cells in rats with dimethylhydrazine-induced colon cancer decreases survival rate.

Transplantation of placenta-derived multipotent cells (PDMCs) is a promising treatment method for many diseases. However, the impact of PDMCs on colon cancer has not yet been studied. PDMCs were obtained from rat placentas by culturing tissue explants. Colon cancer was experimentally induced in male albino Wistar rats by administering 20 mg/kg dimethylhydrazine (DMH) once a week for 20 consecutive weeks. The administration of the PDMCs was performed at the 20th week after the first DMH injection. The number and size of each tumour lesion were calculated in the 5th week after transplantation. The tumour type was determined by standard histological methods. To study the engraftment of PDMCs in the body of rats, the cells were transduced with enhanced green fluorescent protein. Cell engraftment was determined by assessing the presence of EGFP by PCR and immunohistochemistry. Survival of all rats was monitored daily. Allogeneic transplantation of PDMCs to rats at middle phase of DMH-induced colon carcinogenesis did not significantly influence the number of neoplasms and the parameters of mean and total tumour area, but led to an increase in size of the most invasiveness tumours. Intravenous allogeneic transplantation of PDMCs reduced the survival rate of rats with colon cancer by 17 days. PDMCs from rats engrafted into tissues of the normal intestine, tumours, lungs, liver, and spleen of rats for five weeks after intravenous transplantation. These results suggest that intravenous allogeneic transplantation of PDMCs promotes colon cancer progression and has a negative impact on survival of rats.

Naringenin (4,5,7-trihydroxyflavanone) suppresses the development of precancerous lesions via controlling hyperproliferation and inflammation in the colon of Wistar rats.

Colon cancer is a world-wide health problem and one of the most dangerous type of cancer, affecting both men and women. Naringenin (4, 5, 7-trihydroxyflavanone) is one of the major flavone glycoside present in citrus fruits. Naringenin has long been used in Chinese's traditional medicine because of its exceptional pharmacological properties and non-toxic nature. In the present study, we investigated the chemopreventive potential of Naringenin against 1,2-dimethyhydrazine (DMH)-induced precancerous lesions, that is, aberrant crypt foci (ACF) and mucin depleted foci (MDF), and its role in regulating the oxidative stress, inflammation and hyperproliferation, in the colon of Wistar rats. Animals were divided into five groups. In groups 3-5, Naringenin was administered at the dose of 50mg/kg b. wt. orally while in groups 2-4, DMH was administered subcutaneously in the groin at the dose of 20mg/kg b. wt. once a week for first 5weeks and animals were euthanized after 10weeks. Administration of Naringenin ameliorated the development of DMH-induced lipid peroxidation, ROS formation, precancerous lesions (ACF and MDF) and it also reduced the infiltration of mast cells, suppressed the immunostaining of NF-κB-p65, COX-2, i-NOS PCNA and Ki 67 Naringenin treatment significantly attenuated the level of TNF-α and it also prevented the depletion of the mucous layer. Our findings suggest that Naringenin has strong chemopreventive potential against DMH-induced colon carcinogenesis but further studies are warranted to elucidate the precise mechanism of action of Naringenin.

Therapeutic Promise of Dabigatran Etexilate, an Oral Direct Thrombin Inhibitor in a Preclinical Model of Colon Carcinogenesis

Clinical observations suggest that there is activation of the coagulation system in patients of colon cancer. The resulting thrombin is implied in further exacerbation in the progression of colon cancer. We evaluated the effect of dabigatran etexilate (DE), an oral direct thrombin inhibitor in a preclinical model of 1, 2-Dimethylhydrazine (DMH) induced colon carcinogenesis in rats. DE reduced carcinogenesis induced gross morphological changes and colonic edema as compared to induced control. DE treatment significantly reduced levels of VEGF and ERK/MAPK and displayed a significant increase in colonic E-cadherin and reduction in N-cadherin, Twist and mTOR expression. Histopathologically, DE prevented the DMH induced adenocarcinomatous changes in the rat colon. Dual treatment of DE+5FU provided an additive effect as compared to the single treatment schedules of DE and 5FU, respectively. The preclinical study provides preliminary evidences on the promise of DE in treating DMH induced colon carcinogenesis in rats. The study portrays the effective role of DE treatment schedules both alone and in combination with 5FU in abating the parameters associated with progression of colon carcinogenesis expressing amelioration of factors mediating EMT, an important prelude to disease aggression and metastasis. A temporal association was drawn between administration of DE and improvement in colon cancer associated clinical end points. This investigation strongly suggests the role of thrombin in progression of carcinogen induced colon cancer and substantiates the role of direct thrombin inhibitors in treating colon cancer.

Asiatic acid abridges pre-neoplastic lesions, inflammation, cell proliferation and induces apoptosis in a rat model of colon carcinogenesis

The utmost aim of this present study was to investigate the anti-inflammatory, antiproliferative and proapoptotic potential of Asiatic acid (AA) on 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in experimental rats. Rats were divided into six groups and received modified pellet diet for 32 weeks. Group 1 served as control rats. Group 2 received AA (4 mg/kg b.w. p.o.). Group 3–6 rats received 15 DMH (20 mg/kg b.w., s.c.) injections once a week starting from the 4th week. Besides DMH, rats received AA (4 mg/kg b.w. p.o.) in group 4 starting 2 weeks before carcinogen treatment till the end of the last DMH; group 5 starting 2 days after last DMH till the end of the experiment; and group 6 throughout the experiment. Pre-neoplastic lesions, xenobiotic metabolizing enzymes, inflammation, cell proliferation and apoptotic markers were analysed in our study. Our results ascertained AA supplementation to DMH-exposed rats significantly decreased the incidence of aberrant crypt foci (ACF) and phase I xenobiotic enzymes; and increased the phase II xenobiotic enzymes and mucin content as compared to DMH-alone-exposed rats. Moreover the increased expressions of mast cells, argyrophilic nucleolar organizer regions (AgNORs), proliferating cell nuclear antigen (PCNA) and cyclin D1 observed in the DMH-alone-exposed rats were reverted and were comparable with those of the control rats, when treated with AA. Concordantly AA also induced apoptosis by downregulating the expression of Bcl-2 and upregulating Bax, cytochrome c, caspase-3 and -9 in the DMH-alone-exposed rats. Thus AA was able to inhibit DMH-induced colon carcinogenesis by detoxifying the carcinogen, decreasing the preneoplastic lesions by virtue of its anti-inflammatory, antiproliferative and proapoptotic effects. Therefore our findings suggest that AA could be used as an effective chemopreventive agent against DMH induced colon carcinogenesis.