ABSTRACT
Asiatic acid (AA), a pentacyclic triterpenoid, derived from the tropical medicinal plant Centella asiatica is known to exhibit numerous pharmacological properties. We hypothesized that AA will have chemopreventive potential against 1,2-dimethylhydrazine (DMH)-induced experimental colon carcinogenesis in male Wistar rats. Rats were arbitrarily divided into six groups. Group I rats were processed as control. Group II rats received AA (8 mg/kg b.w., p.o.) and groups III-VI rats received subcutaneous injections of DMH (20 mg/kg b.w.) once a week, for the first four weeks. In addition, groups IV-VI rats received AA at the doses of 2, 4 and 8 mg/kg b.w., respectively, for 16 weeks. Our results discovered that supplementation with AA to the DMH-exposed rats significantly decreased the incidence of polyps and Aberrant crypt foci (ACF) as compared to the DMH-alone-exposed rats. Moreover, in the AA-supplemented DMH-exposed rats, we ascertained increased activities of the antioxidants and decreased levels of lipid peroxidation (LPO) in the liver and circulation and enhanced levels of both LPO and antioxidants in the colon, which were altered in the DMH-alone-exposed rats. Furthermore, we also observed altered activities of vitamins C and E and biotransforming enzymes in DMH-alone-exposed rats, which were reversed on AA supplementation. All the observations were supported by our histological findings. Thus, we can conclude that, AA could be used as an effective chemopreventive agent against DMH-induced colon carcinogenesis.
Subject(s)
Anticarcinogenic Agents/therapeutic use , Colon/drug effects , Colonic Neoplasms/prevention & control , Oxidative Stress/drug effects , Pentacyclic Triterpenes/therapeutic use , Precancerous Conditions/prevention & control , 1,2-Dimethylhydrazine/pharmacokinetics , Animals , Anticarcinogenic Agents/administration & dosage , Ascorbic Acid/metabolism , Biotransformation , Catalase/metabolism , Colon/enzymology , Colon/pathology , Colonic Neoplasms/chemically induced , Colonic Neoplasms/enzymology , Colonic Neoplasms/pathology , Dose-Response Relationship, Drug , Male , Pentacyclic Triterpenes/administration & dosage , Precancerous Conditions/chemically induced , Precancerous Conditions/enzymology , Precancerous Conditions/pathology , Rats, Wistar , Superoxide Dismutase/metabolism , Vitamin E/metabolismABSTRACT
Non steroidal anti inflammatory drugs (NSAIDs) are efficacious in chemoprevention of colorectal cancer. Therefore, the potential ability of Etoricoxib, a selective cycloxygenase-2(COX-2) inhibitor and Diclofenac, a preferential COX-2 inhibitor are considered in the chemoprevention of 1, 2-dimethylhydrazine (DMH) induced colon carcinogenesis in rat model. DMH was injected s.c. for six weeks while Etoricoxib and Diclofenac were fed daily orally alone and also in combination with an weekly subcutaneous injection of 1,2-dimethylhydrazine dihydrochloride (DMH) to the rats. After the treatment period of 6 weeks the animals were sacrificed by an overdose of ether anesthesia and the colonic tissues were removed and studied by the FTIR and NMR Spectroscopic techniques to evaluate the changes occurring in the lipid bilayer of colonic membrane lipids. The alterations in wave number of FTIR spectra as well as the chemical shifts of NMR spectra were recorded which signify the modulation of membrane lipids during colon carcinogenesis and possible cancer prevention by the oral administration of NSAIDs in an experimental model of chemical induced colon carcinogenesis (AU)
Los fármacos antiinflamatorios no esteroideos (AINE) son eficaces en la prevención del cáncer colorrectal. Por lo tanto, la capacidad potencial de Etoricoxib, un inhibidor selectivo de la ciclooxigenasa-2(COX-2), y de Diclofenaco, un inhibidor preferencial de la COX-2, se considera en la quimioprevención de la carcinogénesis de colon inducida por 1, 2-dimetilhidracina (DMH) en el modelo murino. Se inyectó s.c. DMH durante 6 semanas a la vez que se administraban diariamente por vía oral Etoricoxib y Diclofenaco solos y en combinación con una inyección s.c. semanal de dihidrocloruro de 1,2-dimetilhidracina (DMH) a las ratas. Después del período de tratamiento de 6 semanas, se sacrificó a los animales mediante una sobredosis de anestesia con éter y se extirpó el tejido colónico para estudio con las técnicas espectroscópicas FTIR y NMR para evaluar los cambios que ocurrieron en la bicapa lipídica de las membranas lipídicas colónicas. Se registraron las alteraciones en el número de onda del espectro FTIR así como las desviaciones químicas del espectro NMR, lo que significa la modulación de los lípidos de membrana durante la carcinogénesis colónica y la posible prevención del cáncer mediante la administración de AINE por vía oral en un modelo experimental de carcinogénesis colónica inducida por un agente químico (AU)
Subject(s)
Animals , Rats , Cyclooxygenase 2 Inhibitors/pharmacokinetics , Colonic Neoplasms/drug therapy , Disease Models, Animal , 1,2-Dimethylhydrazine/pharmacokinetics , Spectrum Analysis/methodsABSTRACT
The present study was designed to evaluate the effects of three non-steroidal anti-inflammatory drugs (NSAIDs) with varying cycloxygenase selectivities on the small intestinal biochemical composition, function and histology during 1, 2-dimethylhydrazine (DMH) administration. Sprague Dawley male rats were divided into five different groups viz: Group 1 (control, vehicle treated), Group 2 (DMH-treated, 30 mg/kg body weight/week in 1 mM EDTA-saline, subcutaneously), Group 3 (DMH + aspirin-60 mg/kg body weight), Group 4 (DMH + celecoxib-6 mg/kg body weight), Group 5 (DMH + etoricoxib-0.64 mg/kg body weight). After six weeks of treatment, brush border membrane was isolated from the jejunum segment of all the groups and changes in the associated enzymes such as sucrase, lactase, maltase, alkaline phosphatase, membrane lipid composition, fluorescence polarizations of diphenylhexatriene, pyrene excimer formation, histological changes and surface characteristics were studied. The results indicated a significant alteration in the enzyme activity as well as changes in the structure and function of the intestine in the presence of the pro-carcinogen, DMH, which suggests the possible chemopreventive efficacy of NSAIDs against the intestinal cancer (AU)
El presente estudio se diseñó para evaluar los efectos de tres fármacos antiinflamatorios no esteroideos (AINE) con diferente selectividad por la ciclooxigenasa sobre la composición bioquímica, la función y la histología del intestino delgado durante la administración de 1,2-dimetilhidracina (DMH). Se distribuyó a ratas macho Sprague Dawley en grupos distintos: Grupo 1 (control, tratado con vehículo), Grupo 2 (tratado con DMH, 30 mg/kg de peso /semana en 1 mM de EDTA-salino, subcutáneo), Grupo 3 (DMH + aspirina-60 mg/kg de peso), Grupo 4 (DMH + celecoxib-6 mg/kg de peso), Grupo 5 (DMH + etoricoxib-0,64 mg/kg de peso). Tras seis semanas de tratamiento, se aisló la membrana en cepillo de un segmento del yeyuno en todos los grupos y se estudiaron los cambios en las enzimas asociadas tales como sucrasa, lactasa, maltasa, fosfatasa alcalina, en la composición lipídica de la membrana, las polarizaciones de fluorescencia del difenilhexatrieno, la formación del excímero pireno, los cambios histológicos y las características de la superficie. Los resultados indican una alteración significativa de la actividad enzimática así como cambios en la estructura y función del intestino en presencia del procarcinógeno DMH, lo que sugiere la posible eficacia quimio-preventiva de los AINE frente al cáncer de intestino (AU)
