ABSTRACT
Arbutin is utilized in traditional remedies to cure numerous syndromes because of its anti-microbial, antioxidant, and anti-inflammatory properties. This study aimed to evaluate chemopreventive effects of arbutin on azoxymethane (AOM)-induced colon aberrant crypt foci (ACF) in rats. Five groups of rats were used: normal control group (rats injected hypodermically with sterile phosphate-buffered saline once per week for two weeks) and groups 2-5, which were subcutaneously inoculated with 15 mg/kg AOM once a week for two weeks. AOM control and 5-fluorouracil (5-FU) control groups were fed 10% Tween orally daily for 8 weeks using a feeding tube. The treated groups were fed 30 and 60 mg/kg arbutin every day for 2 months. ACF from the AOM control group had aberrant nuclei in addition to multilayered cells and an absence of goblet cells. The negative control group displayed spherical cells and nuclei in basal positions. Histological examination revealed a reduced number of AFC cells from colon tissues of the 5-FU reference group. Arbutin-fed animals showed down-regulation of proliferating cell nuclear antigen (PCNA) and up-regulation of Bax protein compared to AOM control. Rats fed with arbutin displayed a significant increase of superoxide dismutase (SOD) and catalase (CAT) activities in colon tissue homogenates compared to the AOM control group. In conclusion, arbutin showed therapeutic effects against colorectal cancer, explained by its ability to significantly decrease ACF, down-regulate PCNA protein, and up-regulate Bax protein. In addition, arbutin significantly increased SOD and CAT, and decreased malondialdehyde (MDA) levels, which might be due to its anti-proliferative and antioxidant properties.
Subject(s)
Aberrant Crypt Foci , Arbutin , Azoxymethane , Proliferating Cell Nuclear Antigen , bcl-2-Associated X Protein , Animals , Aberrant Crypt Foci/chemically induced , Aberrant Crypt Foci/pathology , Aberrant Crypt Foci/prevention & control , Aberrant Crypt Foci/drug therapy , Proliferating Cell Nuclear Antigen/metabolism , Male , Arbutin/pharmacology , Rats , bcl-2-Associated X Protein/metabolism , Colon/drug effects , Colon/pathology , Rats, Wistar , Fluorouracil , CarcinogensABSTRACT
OBJECTIVE: The study's aim was to evaluate Brazilian Brown Propolis (BBP) and Artepillin C (ARC) chemopreventive action in Wistar rats' colons. METHODS: Fifty male Wistar rats were divided into ten experimental groups, including control groups, groups with and without 1,2-dimethylhydrazine (DMH) induction, and BBP, ARC, and ARC enriched fraction (EFR) treatments, for sixteen weeks. Aberrant crypt foci (ACF) were classified as hyperplastic or dysplastic, and proliferating cell nuclear antigen (PCNA) expression was quantified. RESULT: ACF amounts in experimental groups (induced or not) decreased in both colon portions, while the isolated Aberrant Crypt (AC) number increased. Experimental groups of animals showed higher hyperplasia and dysplasia amounts compared with control groups. The ACF dysplastic amount present in groups induced and treated, in both colon portions, had similar values to IDMH (DMH induction group without treatment). In addition, DMH was effective in ACF inducing and there was positive staining for PCNA in basal and upper dysplastic foci portions in all experimental groups, in the mitotic index (MI) evaluation. To conclude, considering all the experimental groups, the one treated with EFR (fraction enriched with ARC) had the lowest rates of cell proliferation. CONCLUSION: BBP and its derivatives prevented crypt cell clonal expansion.
Subject(s)
Aberrant Crypt Foci , Antineoplastic Agents , Colonic Neoplasms , Phenylpropionates , Propolis , Rats , Animals , Male , Rats, Wistar , Colonic Neoplasms/drug therapy , Proliferating Cell Nuclear Antigen/metabolism , Propolis/pharmacology , Propolis/therapeutic use , 1,2-Dimethylhydrazine/toxicity , Brazil , Aberrant Crypt Foci/drug therapy , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , CarcinogensABSTRACT
Mangiferin (MF) is a natural C-glucosylxantone compound that has many substantial curative potentials against numerous illnesses including cancers. The present study's goal is to appraise the chemo preventive possessions of MF on azoxymethane (AOM)-mediated colonic aberrant crypt foci (ACF) in rats. Rats clustered into 5 groups, negative control (A), inoculated subcutaneously with normal saline twice and nourished on 0.5% CMC; groups B-E injected twice with 15 mg/kg azoxymethane followed by ingestion of 0.5% CMC (B, cancer control); intraperitoneal inoculation of 35 mg/kg 5-fluorouracil (C, reference rats) or nourished on 30 mg/kg (D) and 60 mg/kg (E) of MF. Results of gross morphology of colorectal specimens showed significantly lower total colonic ACF incidence in MF-treated rats than that of cancer controls. The colon tissue examination of cancer control rats showed increased ACF availability with bizarrely elongated nuclei, stratified cells, and higher depletion of the submucosal glands compared to MF-treated rats. Mangiferin treatment caused increased regulation of pro-apoptotic (increased Bax) proteins and reduced the ß-catenin) proteins expression. Moreover, rats fed on MF had significantly higher glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), and lower malondialdehyde (MDA) concentrations in their colonic tissue homogenates. Mangiferin supplementation significantly down-shifted pro-inflammatory cytokines (transforming growth factor-α and interleukine-6) and up-shifted anti-inflammatory cytokines (interleukine-10) based on serum analysis. The chemo-protective mechanistic of MF against AOM-induced ACF, shown by lower ACF values and colon tissue penetration, could be correlated with its positive modulation of apoptotic cascade, antioxidant enzymes, and inflammatory cytokines originating from AOM oxidative stress insults.
Subject(s)
Aberrant Crypt Foci , Colorectal Neoplasms , Mangifera , Animals , Rats , Antioxidants/pharmacology , Cytokines , Aberrant Crypt Foci/chemically induced , Aberrant Crypt Foci/drug therapy , Azoxymethane/toxicity , Colorectal Neoplasms/chemically induced , Colorectal Neoplasms/drug therapyABSTRACT
Background and Objectives: Aberrant crypt foci (ACF) are one of the earliest putative preneoplastic and, in some cases, neoplastic lesions in human colons. Many studies have confirmed the reduction of ACFs and colorectal adenomas after treatment with acetylsalicylic acid (ASA) commonly referred to as ASA; however, the minimum effective dose of ASA and the duration of use has not been fully elucidated. The objective of our study was to assess the significance of low dose ASA (75-mg internally once daily) to study the chemopreventive effect of ASA in ACF and adenomas development in patients taking this drug for a minimum period of 10 years. Materials and Methods: Colonoscopy, combined with rectal mucosa staining with 0.25% methylene blue, was performed on 131 patients. The number of rectal ACF in the colon was divided into three groups: ACF < 5; ACF 5−10; and ACF > 10. Patients were divided into two groups: the "With ASA" group (the study group subjects taking ASA 75-mg daily for 10 years); and "Without ASA" group (control group subjects not taking ASA chronically). The incidence of different types of rectal ACF and colorectal polyps in both groups of subjects was analysed and ascertained. Results: Normal ACF was found in 12.3% in the study group vs. 87.7% control group, hyperplastic 22.4% vs. 77.6%, dysplastic 25% vs. 75%, mixed 0% vs. 100%. Treatment with ASA affects the occurrence of colorectal adenomas. The amount of dysplastic ACFs was lower in the study group than in the control group. The increase in dysplastic ACFs decreases with age in both groups, with the increase greater in those not taking ASA. Conclusions: Patients who take persistent, chronic (>10 years) low doses of ASA have a lower total number of all types of rectal ACFs and adenomas compared to the control group.
Subject(s)
Aberrant Crypt Foci , Adenoma , Colorectal Neoplasms , Humans , Aberrant Crypt Foci/drug therapy , Aberrant Crypt Foci/epidemiology , Aberrant Crypt Foci/pathology , Aspirin/therapeutic use , Rectum , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/prevention & control , Colorectal Neoplasms/drug therapy , Adenoma/prevention & control , Adenoma/pathologyABSTRACT
Leukotriene receptor antagonists (LTRA) are widely used drugs for treating allergic asthma, and they have recently been suggested to have a suppressive effect on carcinogenesis and cancer cell proliferation. Aberrant crypt foci (ACF) are considered a reliable surrogate biomarker of colorectal cancer. This prospective study explored the chemopreventive effect of an LTRA on colonic ACF formation and the safety of the medicine in patients as a pilot trial leading to a colorectal cancer chemoprevention trial.This was a nonrandomized, open-label, controlled trial in patients with colorectal ACFs. The participants were allocated to LTRA or observation groups. Patients in the LTRA group received 10 mg of montelukast orally daily for 8 weeks. After the intervention, colonoscopy was performed to evaluate the changes in the number of ACFs.From November 2017 to March 2020, 40 patients were enrolled. The first 30 were assigned to the LTRA group, and the remaining 10 were assigned to the observation group. In the LTRA group, the mean change in the number of ACFs per patient at 8 weeks from baseline was -2.4 ± 2.2, while the mean change in the observation group was 0.4 ± 2.3 (P = 0.002). There were no severe adverse events.This is the first study to explore the effect of LTRAs against colorectal ACF formation in humans. LTRAs are potential candidates for chemoprevention in colorectal cancer. PREVENTION RELEVANCE: We conducted the first LTRA chemoprevention trial for human rectal ACFs, which is considered a surrogate marker of colorectal carcinogenesis. 8-week treatment with LTRA suppressed ACF formation and cell proliferation in colonic epithelium. LTRAs are possible candidates for chemoprevention in colorectal cancer. See related Spotlight, p. 637.
Subject(s)
Aberrant Crypt Foci , Colorectal Neoplasms , Aberrant Crypt Foci/drug therapy , Aberrant Crypt Foci/prevention & control , Carcinogenesis , Chemoprevention , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/prevention & control , Humans , Leukotriene Antagonists/therapeutic use , Prospective StudiesABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Cuscuta reflexa Roxb. (C. reflexa) is a well-known traditional herbal plant, with numerous inherent therapeutic potentials including anticancer, antitumor, antibacterial, analgesic, anthelmintic, laxative and others. Moreover, the anticancer and antitumor potentials of this herb are ongoing with several trails, thus an attempt was made to assess the anticancer and hepatoprotective potentials of traditional C. reflexa herbs. METHOD: The dried ethanolic extract of C. reflexa was tested for acute oral toxicity in the treated animals subsequently their behavioral, neurological, and autonomic profiles changes were observed. The preliminary anti-cancer effects of extracts against 1, 2- Dimethyl hydrazine (DMH) induced animals were assessed through barium enema X-ray, colonoscopy, and Aberrant crypt foci (ACF) studies. The blood samples of the animals (treated and untreated) were collected and their in-vitro histological parameters were evaluated by the experienced technician. RESULTS: It was observed that C. reflexa significantly reduced Disease activity indexing (DAI) level and ACF counting, as well as demonstrated similar activity as of the standard drug 5-Fluorouracil (5-FU). Histopathological results revealed that the apoptotic bodies decreased in the DMH-induced group (group II) during cancer progression while in 5-FU treated (group III) and C. reflexa treated (group IV and V) animals the apoptotic bodies were increased. Inversely, the mitotic bodies increased in group II animals and reduced in group III, IV, and V animals. In the colonic section, DMH-induced cancer assay exhibited significant effects on the levels of hemoglobin, Packed cell volume (PCV), Red blood cell (RBC) counts, Mean corpuscular hemoglobin concentration (MCHC), Mean corpuscular volume (MCV), and Mean cell hemoglobin (MCH), and was found to be less in group II animals whereas administration of C. reflexa efficiently recovered back the loss probably by healing the colon damage/depletion of cancer progression. Moreover, compared to the group II animals, the neutrophil count was within the normal range in C. reflexa administered group. CONCLUSIONS: In the present study, the major hematological parameters significantly increased within DMH treated animals and exhibited extensive damage in the hepatic regions. Moreover, the histopathological findings demonstrated that the C. reflexa extracts potentially reduced the cell proliferation, with no toxicity. The C. reflexa extracts exhibited impending anti-cancer activity as well as protected the hepatic cells and thus could be potentially used in the management of colon or colorectal cancer and hepatic impairments.
Subject(s)
Aberrant Crypt Foci , Colonic Neoplasms , Cuscuta , Toxicity Tests/methods , Aberrant Crypt Foci/drug therapy , Aberrant Crypt Foci/pathology , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Behavior, Animal/drug effects , Cell Proliferation/drug effects , Colon/diagnostic imaging , Colon/drug effects , Colon/pathology , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Drug Monitoring/methods , Drugs, Chinese Herbal/pharmacology , Hepatocytes/drug effects , Hepatocytes/pathology , Mice , Plant Extracts/pharmacologyABSTRACT
Colorectal cancer (CRC) is the third leading type of adult cancer in both genders with high morbidity and mortality worldwide. Even though the discovery of many antineoplastic drugs for CRC, the current therapy is not adequately efficient.This study was designed to investigate the effect and mechanism of Piclamilast (PIC), a selective PDE4 inhibitor, on a DMH-induced colorectal cancer (CRC) rat model. The rats were grouped (n = 10) into group 1 (control), group 2 (PIC 3 mg/kg, p.o.), groups 3-5 received DMH (20 mg/kg/week, S.C.), and groups 4 and 5 received PIC (1 and 3 mg/kg/day, p.o.) for 15 weeks. The DMH treatment increased aberrant crypt foci (ACF), Proliferating cell nuclear antigen (PCNA), and TBARS levels, along with decreased antioxidant defenses (GSH, GSH-Px, and catalase). Increased NF-κß expression and inflammatory cytokines were also evident. PIC dose-dependently reduced ACF and restored oxidative stress and inflammatory markers favorably. Moreover, PIC in its large, tested dose only significantly increased the intracellular level of cAMP and suppressed the activation of Ras and PI3K and its downstream Akt/mTOR signaling. Furthermore, PIC promoted CRC apoptosis, and increased the gene expression of the apoptotic factors, caspase-3 and Bax, and decreased the anti-apoptotic factor Bcl-2. The results of this study show that PIC may be a promising therapeutic agent for the treatment of CRC. PIC might inhibit the proliferation of CRC cells and induce apoptosis via multiple mechanisms that involve its antioxidant effect and inhibition of NF-κß and Ras/PI3K/Akt/mTOR signaling.
Subject(s)
1,2-Dimethylhydrazine/antagonists & inhibitors , 1,2-Dimethylhydrazine/toxicity , Benzamides/pharmacology , Colonic Neoplasms/drug therapy , Colonic Neoplasms/metabolism , Phosphodiesterase 4 Inhibitors/pharmacology , Pyridines/pharmacology , Aberrant Crypt Foci/drug therapy , Aberrant Crypt Foci/metabolism , Aberrant Crypt Foci/pathology , Animals , Apoptosis/drug effects , Apoptosis/genetics , Cell Proliferation/drug effects , Colonic Neoplasms/chemically induced , Disease Models, Animal , Male , Oxidative Stress/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Wistar , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , ras Proteins/metabolismABSTRACT
Polyphenon E (Poly E) is a green tea polyphenol preparation whose most active component is epigallocatechin gallate (EGCG). We studied the cancer preventive efficacy and safety of Poly E in subjects with rectal aberrant crypt foci (ACF), which represent putative precursors of colorectal cancers. Eligible subjects had prior colorectal advanced adenomas or cancers, and had ≥5 rectal ACF at a preregistration chromoendoscopy. Subjects (N = 39) were randomized to 6 months of oral Poly E (780 mg EGCG) daily or placebo. Baseline characteristics were similar by treatment arm (all P >0.41); 32 of 39 (82%) subjects completed 6 months of treatment. The primary endpoint was percent reduction in rectal ACF at chromoendoscopy comparing before and after treatment. Among 32 subjects (15 Poly E, 17 placebo), percent change in rectal ACF number (baseline vs. 6 months) did not differ significantly between study arms (3.7% difference of means; P = 0.28); total ACF burden was also similar (-2.3% difference of means; P = 0.83). Adenoma recurrence rates at 6 months were similar by arm (P > 0.35). Total drug received did not differ significantly by study arm; 31 (79%) subjects received ≥70% of prescribed Poly E. Poly E was well tolerated and adverse events (AE) did not differ significantly by arm. One subject on placebo had two grade 3 AEs; one subject had grade 2 hepatic transaminase elevations attributed to treatment. In conclusion, Poly E for 6 months did not significantly reduce rectal ACF number relative to placebo. Poly E was well tolerated and without significant toxicity at the dose studied. PREVENTION RELEVANCE: We report a chemoprevention trial of polyphenon E in subjects at high risk of colorectal cancer. The results show that polyphenon E was well tolerated, but did not significantly reduce the number of rectal aberrant crypt foci, a surrogate endpoint biomarker of colorectal cancer.
Subject(s)
Aberrant Crypt Foci/drug therapy , Catechin/analogs & derivatives , Colorectal Neoplasms/drug therapy , Neoplasm Recurrence, Local/prevention & control , Aberrant Crypt Foci/diagnosis , Aberrant Crypt Foci/pathology , Aged , Catechin/administration & dosage , Catechin/adverse effects , Colon/diagnostic imaging , Colon/drug effects , Colon/pathology , Colonoscopy , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/pathology , Female , Follow-Up Studies , Humans , Intestinal Mucosa/diagnostic imaging , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , Male , Middle Aged , Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/pathology , Placebos/administration & dosage , Placebos/adverse effects , Rectum/diagnostic imaging , Rectum/drug effects , Rectum/pathology , Treatment OutcomeABSTRACT
BACKGROUND: The incidence and mortality rates of colorectal cancer (CRC) continue to increase worldwide. Therefore, new preventive strategies are needed to lower the burden of this disease. Previous studies reported that aspirin could suppress the development of sporadic colorectal adenoma. In addition, metformin is a biguanide derivative that is long widely used for the treatment of diabetes mellitus and has recently been suggested to have a suppressive effect on carcinogenesis and cancer cell growth. Both drugs exhibit a chemopreventive effect, but their efficacy is limited. Aberrant crypt foci (ACF), defined as lesions containing crypts that are larger in diameter and stain more darkly with methylene blue than normal crypts, are more prevalent in patients with cancer and adenomas, and considered a reliable surrogate biomarker of CRC. Thus, we designed a prospective trial as a preliminary study prior to a CRC chemoprevention trial to evaluate the chemopreventive effect of aspirin combined with metformin on colorectal ACF formation in patients scheduled for polypectomy. METHODS: This study is a double-blind randomized controlled trial that will be conducted in patients with both colorectal ACF and colorectal polyps scheduled for polypectomy. Eligible patients will be recruited for the study and the number of ACF in the rectum will be counted at the baseline colonoscopy. Then, the participants will be allocated to one of the following two groups; the aspirin plus placebo group or the aspirin plus metformin group. Patients in the aspirin plus placebo group will receive oral aspirin (100 mg) and placebo for 8 weeks, and those in the aspirin plus metformin group will receive oral aspirin (100 mg) and metformin (250 mg) for 8 weeks. After 8 weeks of administration, polypectomy will be performed to evaluate changes in the number of ACF, and the cell-proliferative activity in the normal colorectal mucosa and colorectal polyps. DISCUSSION: This is the first study proposed that will explore the effect of aspirin combined with metformin on the formation of colorectal ACF in humans. TRIAL REGISTRATION: This trial has been registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000028259 . Registered 17 July 2017.
Subject(s)
Aberrant Crypt Foci/drug therapy , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Aspirin/therapeutic use , Colorectal Neoplasms/drug therapy , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , Aberrant Crypt Foci/pathology , Colorectal Neoplasms/pathology , Double-Blind Method , Drug Therapy, Combination , Humans , Prognosis , Prospective Studies , Randomized Controlled Trials as TopicABSTRACT
INTRODUCTION: Aberrant Crypt (AC) and Aberrant Crypt Focus (ACF) are considered pre-neoplasic lesions, ranging from hyperplasia to different degrees of dysplasia in the colon. This work aimed to evaluate and quantify the chemopreventive activity of Zingiber officinale essential oil in the colorectal region of Wistar rats. MATERIALS AND METHODS: We extracted the essential oil from ginger rhizomes and carried out ACF induction, in rats, with 1.2 Dimethylhydrazine (DMH) at a 20 mg/kg dose. The experimental groups were GI (negative control); GII (positive induction control); GIII (DMH + essential oil); GIV (DMH +5-Florouracil) and GV (essential oil). The histological techniques used were methylene blue, hematoxylin-eosin (HE) dyeing, and immunohistochemistry (IHQ). RESULTS: The major essential oil compounds were citral (17.25%), δ-citral (10.25%), camphene (9.55%), α-zingiberene (7.57%), nerol (6.37%) and plelandrene (6.83%). For the presence of AC or ACF, we did not observe them in GI and GV, while in GII and GIII, they were observed, in high values, in both regions, but only in the distal region, there was a significant difference between them. For GIV, for both regions, there were significant lower numbers of AC when compared to GIII. As observed, with HE, there were hyperplastic and dysplastic ACF in the proximal and distal portions of the colon. For IHQ analyses, there were positively PCNA antibody marked cells in all experimental groups. Yet, there was no significant correlation of mitotic index among them. Moreover, the results of GIII compared to GIV were very similar. CONCLUSION: In this sense, the Zingiber officinale essential oil has good antioxidant potential because it presents a mixture of monoterpene and sesquiterpene compounds. Thus, it is able to develop a chemoprotective effect, as it presented similar results to the standard drug, showing cell proliferation control.
Subject(s)
1,2-Dimethylhydrazine/toxicity , Aberrant Crypt Foci/drug therapy , Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Oils, Volatile/pharmacology , Zingiber officinale/chemistry , Aberrant Crypt Foci/chemically induced , Aberrant Crypt Foci/pathology , Animals , Colorectal Neoplasms/chemically induced , Colorectal Neoplasms/pathology , Male , Rats , Rats, WistarABSTRACT
BACKGROUND AND PURPOSE: This study subjected a rat model to the extracts of muscle and shell tissues from Portunus segnis to assess their therapeutic effects on the HT-29 colon cancer cells as well as on colonic Aberrant Crypt Foci (ACF) induced by Azoxymethane (AOM). METHODS: The cell line was exposed to the extracts to compare the cytotoxicity of hexane, butanol, ethyl acetate, and water extract of muscle and ethanolic extract of the shell. Male rats (n=40) were assigned into control, positive, negative, and treatment groups. The animals were injected with AOM, except the control group, and then exposed to 250 and 500mg/kg of the crude extracts. Immunohistochemical localization of Bax and Bcl-2, as well as ACF and antioxidant enzymes, were evaluated in the rat colon. RESULTS: The butanolic muscle extract and ethanolic shell one demonstrated an IC50 of 9.02±0.19µg/ml and 20.23±0.27µg/ml towards the cell line, respectively. Dietary exposure inhibited the ACF formation and crypt multiplicity in the colon compared to the cancer control group. The activity of SOD and CAT increased, while that of MDA decreased. The expression of Bax and Bcl-2 increased and decreased, respectively. CONCLUSION: Taken together, the results show that both extractions were suggested to be suppressive to AOMinduced colon cancer.
Subject(s)
Aberrant Crypt Foci/drug therapy , Antineoplastic Agents/pharmacology , Antioxidants/pharmacology , Brachyura/chemistry , Colorectal Neoplasms/drug therapy , Muscles/chemistry , Aberrant Crypt Foci/chemically induced , Aberrant Crypt Foci/pathology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Antioxidants/chemistry , Antioxidants/isolation & purification , Azoxymethane/administration & dosage , Biphenyl Compounds/antagonists & inhibitors , Cell Proliferation/drug effects , Colorectal Neoplasms/chemically induced , Colorectal Neoplasms/pathology , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Injections, Intradermal , Male , Molecular Structure , Neoplasms, Experimental/chemically induced , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Picrates/antagonists & inhibitors , Rats , Rats, Wistar , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, was shown to act synergistically with a NSAID for chemoprevention of colorectal neoplasia. We determined the efficacy and safety of DFMO plus aspirin for prevention of colorectal adenomas and regression of rectal aberrant crypt foci (ACF) in patients with prior advanced adenomas or cancer. A double-blinded, placebo-controlled trial was performed in 104 subjects (age 46-83) randomized (1:1) to receive daily DFMO (500 mg orally) plus aspirin (325 mg) or matched placebos for one year. All polyps were removed at baseline. Adenoma number (primary endpoint) and rectal ACF (index cluster and total) were evaluated at a one year colonoscopy. ACF were identified by chromoendoscopy. Toxicity was monitored, including audiometry. Eighty-seven subjects were evaluable for adenomas or ACF modulation (n = 62). At one year of treatment, adenomas were detected in 16 (38.1%) subjects in the DFMO plus aspirin arm (n = 42) versus 18 (40.9%) in the placebo arm (n = 44; P = 0.790); advanced adenomas were similar (n = 3/arm). DFMO plus aspirin was associated with a statistically significant reduction in the median number of rectal ACF compared with placebo (P = 0.036). Total rectal ACF burden was also reduced in the treatment versus the placebo arm relative to baseline (74% vs. 45%, P = 0.020). No increase in adverse events, including ototoxicity, was observed in the treatment versus placebo arms. While adenoma recurrence was not significantly reduced by one year of DFMO plus aspirin, the drug combination significantly reduced rectal ACF number consistent with a chemopreventive effect.
Subject(s)
Aberrant Crypt Foci/drug therapy , Adenoma/drug therapy , Aspirin/therapeutic use , Colorectal Neoplasms/drug therapy , Eflornithine/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Aberrant Crypt Foci/complications , Aberrant Crypt Foci/pathology , Adenoma/complications , Adenoma/pathology , Aged , Aged, 80 and over , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antineoplastic Agents/therapeutic use , Colorectal Neoplasms/complications , Colorectal Neoplasms/pathology , Double-Blind Method , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/complications , Neoplasm Recurrence, Local/pathology , PrognosisABSTRACT
PURPOSE: Callistemon citrinus (Curtis) Skeels is a shrub native of Australia. In spite of containing an important number of bioactive compounds (1,8-cineole, limonene and α-terpineol) recognized as a potential chemotherapeutic agents, it is only used as an ornamental plant in Mexico. This study investigated the chemopreventive effect of C. citrinus leaves extract on 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rats. METHODS: Twenty-four rats were divided into 3 groups of eight rats. Group 1 served as negative control, groups 2 and 3 were given subcutaneous injections of DMH (65 mg/kg b.w.) twice a week the first 2 weeks, and then one the third week. In addition, group 3 was administrated with leaves extracts (250 mg/kg b.w., orally daily) during the 22 weeks of the experiment. Animals were killed and the presence of colon tumors and aberrant crypt foci (ACF) were scored for number and distribution pattern along the colon. The activity of two-phase II enzymes quinone reductase (QR) and glutathione S-transferase (GST) was determined in the liver and three segments of the colon: proximal, middle and distal. RESULTS: The results show that rats feed with C. citrinus leaves extract significantly reduced the size of tumors, the number of ACF and the crypt multiplicity. Additionally, C. citrinus leaves extract increased or maintained the activity of QR and GST in the different tissues as compared with DHM-treated group (p > 0.05). CONCLUSION: This study demonstrates that Callistemon citrinus extract could have a chemopreventive effect against colon carcinogenesis.
Subject(s)
Colonic Neoplasms/prevention & control , Myrtaceae/chemistry , Plant Extracts/pharmacology , 1,2-Dimethylhydrazine , Aberrant Crypt Foci/chemically induced , Aberrant Crypt Foci/drug therapy , Aberrant Crypt Foci/pathology , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Body Weight/drug effects , Carcinogens , Colonic Neoplasms/chemically induced , Colonic Neoplasms/enzymology , Colonic Neoplasms/pathology , Disease Models, Animal , Male , Random Allocation , Rats , Rats, WistarABSTRACT
Zinc is a trace element widely known for its marked antioxidant properties. To gain more insight into the site- and time- specific mechanisms by which it induces chemoprevention, this study was elaborated over a pre-cancerous model of colon carcinogenesis. Colon cancer was induced by 1,2-dimethylhydrazine (DMH) in mice (20â¯mg/kg for 2 weeks) and groups of animals were supplemented with or without zinc sulfate (ZnSO4, 200â¯mg/L) in drinking water for 4, 10 or 14 weeks. Colon tissues were collected for pathological observation, analyzing aberrant crypt (AC) and aberrant crypt foci (ACF) formations, multiplicity and distribution. Similarly, histological assessment and mucin production, as well as oxidative stress markers estimation was performed for the different groups. Results showed a significant increase in ACF and AC numbers, ACF multiplicity and demonstrated stronger distal occurrence than in the proximal after DHM administration. Histopathological analysis presented marked structural alterations and mucin loss in the distal than the proximal colons. A significant increase in myeloperoxidase (MPO), nitric oxide (NO), L-ornithine and malondialdehyde (MDA) levels was observed followed by a significant decrease in antioxidant markers (superoxide dismutase (SOD), catalase (CAT) and reduced glutathione (GSH)). Oral ZnSO4 supplementation (continuous or partial) induced significant decrease in ACF, AC numbers and multiplicity, restored histological architecture and mucin production, and a significant decrease in proinflammatory markers while it reduced antioxidants to normal levels. From this study, insight was obtained on the use of ZnSO4 as a chemopreventive agent and shed light on its potential, as a supplement in nutraceutical approaches.
Subject(s)
Aberrant Crypt Foci/drug therapy , Colonic Neoplasms/drug therapy , Zinc Sulfate/pharmacology , 1,2-Dimethylhydrazine/toxicity , Aberrant Crypt Foci/chemically induced , Aberrant Crypt Foci/metabolism , Animals , Anticarcinogenic Agents/pharmacology , Antioxidants/metabolism , Colonic Neoplasms/chemically induced , Colonic Neoplasms/metabolism , Enzymes/metabolism , Mice , Neoplasms, Experimental/chemically induced , Oxidative Stress/drug effects , Precancerous Conditions/chemically induced , Precancerous Conditions/drug therapy , Precancerous Conditions/pathologyABSTRACT
2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside (THSG) has been shown to have antioxidative and anti-inflammatory effects. Oxidative and inflammatory reactions are related to the development of colorectal carcinoma (CRC). In the present study, we characterized the preventive activities of THSG on colon carcinogenesis using the azoxymethane- (AOM-) mediated rat colon carcinogenesis model. F344 male rats were randomly divided into 5 groups (untreated and AOM model rats treated with or without THSG at 30, 150, or 250 mg/kg) after which the numbers of aberrant crypt foci (ACF) were assessed in the colon tissues of all rats. The expressions of nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2), matrix metalloproteinase proteins (MMPs), and carcinoembryonic antigen (CEA) were measured as effective early predictors of CRC using western blot analysis. Treatment with THSG (150 or 250 mg/kg) induced a 50% reduction in total colonic ACF formation (P < 0.05). Furthermore, our results revealed a downregulation of CEA and NF-κB protein levels in the reduced number of ACF elicited by treatment with THSG, whereas levels of COX-2 and MMPs proteins were not changed. Collectively, THSG may be a promising natural lead compound or drug candidate for treating early phases of CRC.
Subject(s)
Aberrant Crypt Foci/drug therapy , Anticarcinogenic Agents/administration & dosage , Colorectal Neoplasms/drug therapy , Glucosides/administration & dosage , Stilbenes/administration & dosage , Aberrant Crypt Foci/chemically induced , Aberrant Crypt Foci/genetics , Aberrant Crypt Foci/pathology , Animals , Azoxymethane/toxicity , Carcinoembryonic Antigen/genetics , Carcinogens/toxicity , Colorectal Neoplasms/chemically induced , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Cyclooxygenase 2/genetics , Disease Models, Animal , Gene Expression Regulation, Neoplastic/drug effects , Humans , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , NF-kappa B/genetics , RatsABSTRACT
The objective of this study was to evaluate the effect of Moquiniastrum polymorphum ssp floccosum ethanolic extract (MPEE) on 1,2 dimethylhydrazine (DMH)-induced colorectal carcinogenesis in mice. Forty-two male Swiss mice (Mus musculus) were subdivided into six groups (N = 7/group): negative control, DMH, MPEE, pre-treatment, simultaneous, and post-treatment. Results showed that MPEE has antigenotoxic potential on the tested protocols pre- and silmultaneous treatment, and the percent damage reductions (%DRs) were 81.88 and 93.12%, respectively. The micronucleus test demonstrated that MPEE has great antimutagenic activity, with %DRs higher than 77.09 in the associated groups. The aberrant crypt focus assay demonstrated anticarcinogenic potential of MPEE as the associated groups showed %DRs that ranged from 62.13 to 95.14%. The study shows that MPEE is nontoxic and has chemopreventive and anticarcinogenic activity, thus it may prove to be a promising medicinal plant in view of its demonstrated properties.
Subject(s)
1,2-Dimethylhydrazine/toxicity , Aberrant Crypt Foci/drug therapy , Asteraceae/chemistry , Colorectal Neoplasms/drug therapy , Ethanol/administration & dosage , Aberrant Crypt Foci/prevention & control , Animals , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/pharmacology , Colorectal Neoplasms/chemically induced , Colorectal Neoplasms/prevention & control , DNA Damage/drug effects , Ethanol/pharmacology , Male , Mice , Micronucleus Tests , Plant Extracts/administration & dosage , Plant Extracts/chemistry , Plant Extracts/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
In recent years, the consumption of vegetal-source proteins has been studied to determine their preventing effect on the development of several chronic diseases. The initial purpose of this report was to determine the effect of a hypercholesterolemic diet (HCD) given to mice, alone or with azoxymethane (AOM), on various obesity biochemical biomarkers, as well as on the induction of colon aberrant crypts (aberrant crypt foci; ACF). At the end of the 5-week assay, animals fed the HCD showed alterations in the level of total cholesterol, high- and low-density lipoproteins, and in the Atherogenic Index; besides, a significant elevation was observed in the number of ACF. Our second aim was to examine the effect of a Faba Protein Hydrolyzate (FPH) on mice fed the HCD. We first obtained protein hydrolyzates from the seeds of Vicia faba, determined the in vitro antioxidant potential with two tests, and, subsequently, evaluated the effect on obesity biomarkers and on the number of ACF. In the first case, we found that, generally, the best protective effect was obtained with the low dose of FPH (10 mg/kg) administered to animals fed the HCD, and injected AOM. With respect to the number of ACF, we observed that this dose was more effective, inhibiting such lesions to almost the level determined for the normocholesterolemic diet (NCD). Therefore, our results demonstrated the relevance of a HCD to develop anomalies in obesity biomarkers in mouse, as well as to increase the number of precarcinogenic lesions. Our results also showed a protective response with the administration of FPH, particularly with a specific dose, suggesting the need for extending research on the matter by widening the spectra of doses, in order to clearly define its potential to counteract the damage induced by the HCD, as well as to confirm if antioxidation in mice was involved in such an effect.
Subject(s)
Anticarcinogenic Agents/pharmacology , Protein Hydrolysates/pharmacology , Vicia faba/chemistry , Aberrant Crypt Foci/drug therapy , Aberrant Crypt Foci/etiology , Animals , Anticarcinogenic Agents/analysis , Antioxidants/analysis , Antioxidants/pharmacology , Azoxymethane/administration & dosage , Azoxymethane/adverse effects , Cholesterol, Dietary/administration & dosage , Cholesterol, Dietary/adverse effects , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/etiology , Diet , Disease Models, Animal , Male , Mice , Mice, Inbred ICR , Plant Extracts/analysis , Plant Extracts/pharmacology , Protein Hydrolysates/analysisABSTRACT
The aim of this study was to investigate the efficacy of a Berberis integerrima hydroalcoholic extract as a chemotherapeutic agent in colon carcinogenesis in the rat induced by 1,2-dimethyl hydrazine (DMH). Male Wistar rats were divided into five groups: a negative control group without DMH treatment; a control group injected DMH (20 mg/kg b.w); two groups receiving B. integerrima extract (50 and 100 mg/kg b.w), concomitant with injected DMH, as chemotherapeutic groups; a positive control group receiving 5-fluorouracil (5-FU) along with DMH. The effects of the extracts were determined by assessment of hepatic malondialdehyde (MDA), glutathione (GSH), ferric reducing ability of plasma (FRAP), and the activities of hepatic glutathione S-transferase and cytochrome P450 (GST and CYP450). Additionally, colon tissues were assessed for colonic ß-catenin and histopathological analysis. In DMH-treated rats, the extracts partially normalized the levels of FRAP, CYP450, ß-catenin, and GST. Likewise, formation of aberrant crypt foci (ACF) in colon tissue of DMH-treated was reduced by the extracts. Thus, the extracts possess chemotherapeutic activity against colon carcinogenesis.
Subject(s)
Berberis/chemistry , Colonic Neoplasms/drug therapy , Disease Models, Animal , Plant Extracts/pharmacology , 1,2-Dimethylhydrazine , Aberrant Crypt Foci/drug therapy , Aberrant Crypt Foci/metabolism , Animals , Carcinogens , Colon/drug effects , Colon/metabolism , Colon/pathology , Colonic Neoplasms/chemically induced , Colonic Neoplasms/metabolism , Cytochrome P-450 Enzyme System/metabolism , Ethanol/chemistry , Glutathione/metabolism , Glutathione Transferase/metabolism , Liver/drug effects , Liver/metabolism , Liver/pathology , Male , Malondialdehyde/metabolism , Phytotherapy , Plant Extracts/chemistry , Rats, Wistar , Treatment Outcome , Water/chemistry , beta Catenin/metabolismABSTRACT
We have previously shown that ethanolic extract from bark (EEB) of Salix aegyptiaca (Musk Willow) can inhibit proliferation and motility and induce apoptosis in colon cancer cells. Tandem mass spectrometry revealed EEB to be rich in catechin, catechol, and salicin. The present study investigated the chemopreventive effect of HPLC-fingerprinted EEB on 1,2-dimethylhydrazine (DMH)-induced aberrant crypt foci (ACF) formation in mice. DMH (20 mg/kg body weight) was weekly injected subcutaneously to mice for the first 2 weeks. EEB (100 and 400 mg/kg body weight) was provided orally from the 7th to 14th week, after which colon tissues were evaluated histologically and biochemically. DMH treatment induced high number of ACF; EEB significantly reduced the number and multiplicity of ACF, along with a restoration in goblet cells and mucin accumulation. EEB supplementation improved the markers of inflammation (myeloperoxidase and neutrophil infiltration) and oxidative stress. More importantly, EEB amplified apoptosis of neoplastic cells in the colon mucosa of DMH-treated mice. It also lowered levels of markers for early transformation events such as EGFR, nuclear ß-catenin, and COX-2 in colon cancer cell lines HT-29 and HCT-116. The innocuity of EEB (up to 1600 mg/kg) to mice reinforces its potential as a chemopreventive agent.
Subject(s)
1,2-Dimethylhydrazine/toxicity , Aberrant Crypt Foci/drug therapy , Anticarcinogenic Agents/pharmacology , Colonic Neoplasms/prevention & control , Plant Extracts/pharmacology , Salix/chemistry , Aberrant Crypt Foci/chemically induced , Aberrant Crypt Foci/pathology , Animals , Anticarcinogenic Agents/chemistry , Carcinogens/toxicity , Chromatography, High Pressure Liquid , Colonic Neoplasms/chemically induced , Colonic Neoplasms/pathology , Ethanol/chemistry , HCT116 Cells/drug effects , Humans , Inhibitory Concentration 50 , Male , Mice , Oxidative Stress/drug effects , Plant Bark/chemistry , Plant Extracts/chemistryABSTRACT
Non-steroidal anti-inflammatory drugs (NSAIDs) are emerging as novel chemopreventive agents against a variety of cancers owing to their capability in blocking the tumor development by cellular proliferation and by promoting apoptosis. Inflammation is principal cause of colon carcinogenesis. A missing link between inflammation and cancer could be the activation of NF-κB, which is a hallmark of inflammatory response, and is commonly detected in malignant tumors. Therefore, targeting pro-inflammatory cyclooxygenase enzymes and transcription factors will be profitable as a mechanism to inhibit tumor growth. In the present study, we have studied the role of various pro-inflammatory enzymes and transcription factors in the development of the 1,2-dimethylhydrazine dihydrochloride (DMH)-induced colorectal cancer and also observed the role of three NSAIDs, viz., Celecoxib, Etoricoxib and Diclofenac. Carcinogenic changes were observed in morphological and histopathological studies, whereas protein regulations of various biomolecules were identified by immunofluorescence analysis. Apoptotic studies was done by TUNEL assay and Hoechst/PI co-staining of the isolated colonocytes. It was found that DMH-treated animals were having an over-expression of pro-inflammatory enzymes, aberrant nuclear localization of activated cell survival transcription factor, NF-κB and suppression of anti-inflammatory transcription factor PPAR-γ, thereby suggesting a marked role of inflammation in the tumor progression. However, co-administration of NSAIDs has significantly reduced the inflammatory potential of the growing neoplasm.