RESUMEN
Cachexia is a multifactorial syndrome characterized by profound involuntary weight loss, fat depletion, skeletal muscle wasting, and asthenia; all symptoms are not entirely attributable to inadequate nutritional intake. Adipose tissue and skeletal muscle loss during cancer cachexia development has been described systematically. The former was proposed to precede and be more rapid than the latter, which presents a means for the early detection of cachexia in cancer patients. Recently, pioglitazone (PGZ) was proposed to exhibit anti-cancer properties, including a reduction in insulin resistance and adipose tissue loss; nevertheless, few studies have evaluated its effect on survival. For greater insight into a potential anti-cachectic effect due to PGZ, 8-week-old male Wistar rats were subcutaneously inoculated with 1 mL (2×107) of Walker 256 tumor cells. The animals were randomly assigned to two experimental groups: TC (tumor + saline-control) and TP5 (tumor + PGZ/5 mg). Body weight, food ingestion and tumor growth were measured at baseline and after removal of tumor on days 7, 14 and 26. Samples from different visceral adipose tissue (AT) depots were collected on days 7 and 14 and stored at -80o C (5 to 7 animals per day/group). The PGZ treatment showed an increase in the survival average of 27.3% (P< 0.01) when compared to TC. It was also associated with enhanced body mass preservation (40.7 and 56.3%, p< 0.01) on day 14 and 26 compared with the TC group. The treatment also reduced the final tumor mass (53.4%, p<0.05) and anorexia compared with the TC group during late-stage cachexia. The retroperitoneal AT (RPAT) mass was preserved on day 7 compared with the TC group during the same experimental period. Such effect also demonstrates inverse relationship with tumor growth, on day 14. Gene expression of PPAR-γ, adiponectin, LPL and C/EBP-α from cachectic rats was upregulated after PGZ. Glucose uptake from adipocyte cells (RPAT) was entirely re-established due to PGZ treatment. Taken together, the results demonstrate beneficial effects of PGZ treatment at both the early and final stages of cachexia.
Asunto(s)
Carcinoma 256 de Walker/tratamiento farmacológico , Tiazolidinedionas/uso terapéutico , Adiponectina/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Caquexia/patología , Carcinoma 256 de Walker/mortalidad , Carcinoma 256 de Walker/patología , Línea Celular Tumoral , Ingestión de Alimentos/efectos de los fármacos , Masculino , PPAR gamma/metabolismo , Pioglitazona , Ratas , Ratas Wistar , Tasa de Supervivencia , Tiazolidinedionas/farmacología , Trasplante HomólogoRESUMEN
The flavonoid naringin is a polyphenolic compound that naturally occurs in citrus. Patients with cancer generally present features of malnutrition and cachexia. Levels of the proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) are raised in patients with cancer. This study was designed to analyze the in vivo effect of naringin in the therapeutic treatment of rats bearing Walker 256 carcinosarcoma (W256). Rats were treated intraperitoneally with different doses of naringin (10, 25 and 35 mg/kg), for 50 days. At 25 mg/kg, naringin inhibited tumor growth by ~75%. With this treatment, TNF-α and IL-6 levels decreased (p<0.05) in comparison with the control. In addition, two rats presented complete tumor regression. Inhibition of tumor growth, survival increase and the reduction of TNF-α and IL-6 levels in rats bearing W256 treated with naringin strongly suggest that this compound has potential as an anticarcinogenic drug.
Asunto(s)
Carcinoma 256 de Walker/tratamiento farmacológico , Carcinoma 256 de Walker/metabolismo , Flavanonas/uso terapéutico , Interleucina-6/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Caquexia/tratamiento farmacológico , Caquexia/metabolismo , Carcinoma 256 de Walker/mortalidad , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratas , Ratas Wistar , Tasa de SupervivenciaRESUMEN
Fish oil supplementation has been shown to improve the cachectic state of tumor-bearing animals and humans. Our previous study showed that fish oil supplementation (1 g per kg body weight per day) for 2 generations had anticancer and anticachetic effects in Walker 256 tumor-bearing rats as demonstrated by reduced tumor growth and body weight loss and increased food intake and survival. In this study, the effect of fish oil supplementation for 2 generations on membrane integrity, proliferation capacity, and CD4/CD8 ratio of lymphocytes isolated from mesenteric lymph nodes, spleen, and thymus of Walker 256 tumor-bearing animals was investigated. We also determined fish oil effect on plasma concentration and ex vivo production of cytokines [tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-4 (IL-4), IL-6, and IL-10]. Lymphocytes from thymus of tumor-bearing rats presented lower viability, but this change was abolished by fish oil supplementation. Tumor growth increased proliferation of lymphocytes from all lymphoid organs, and fish oil supplementation abolished this effect. Ex vivo production of TNF-alpha and IL-6 was reduced in supplemented animals, but IL-4 and IL-10 secretion was stimulated in both nontumor and tumor-bearing rats. IL-10 and IFN-gamma plasma levels was also decreased in supplemented animals. These results suggest that the anticachetic effects of fish oil supplementation for a long period of time (2 generations) in Walker 256 tumor-bearing rats may be associated to a decrease in lymphocyte function as demonstrated by reduced viability, proliferation capacity, and cytokine production.
Asunto(s)
Anticarcinógenos/administración & dosificación , Caquexia/prevención & control , Carcinoma 256 de Walker/complicaciones , Carcinoma 256 de Walker/fisiopatología , Aceites de Pescado/administración & dosificación , Activación de Linfocitos , Linfocitos/fisiología , Animales , Caquexia/etiología , Caquexia/inmunología , Carcinoma 256 de Walker/inmunología , Carcinoma 256 de Walker/mortalidad , Membrana Celular/metabolismo , Proliferación Celular , Supervivencia Celular , Citocinas/sangre , Citocinas/metabolismo , Femenino , Ganglios Linfáticos/citología , Activación de Linfocitos/inmunología , Linfocitos/metabolismo , Masculino , Trasplante de Neoplasias , Ratas , Ratas Wistar , Bazo/citología , Timo/citología , Timo/metabolismo , Pérdida de PesoRESUMEN
BACKGROUND & AIMS: Cancer cachexia affects intermediary metabolism with intense and general catabolism. Walker 256 tumor is a model injected either subcutaneously (Sc) or intraperitoneally (Ip), with different metabolic features. Beta-hydroxy beta-methylbutyrate (HMbeta) is a leucine metabolite with anti-catabolic properties, the aim of this study being to investigate its effects on metabolic parameters in both tumor models. METHODS: Controls (subcutaneous control group (ScC) and intraperitoneal control group (IpC)) and supplemented animals (subcutaneous supplemented group (ScS) and intraperitoneal supplemented group (IpS)) showed these results. RESULTS: Protein Sc values were (47.8%) lower than Ip groups. Sc group fat content was (65.16%) higher than Ip groups. Liver glycogen value for Sc groups was (38.4%) higher than Ip groups. Muscle glycogen value for Sc groups were (2.75 times) higher than Ip groups. Corticosterone and insulin values were lower (44.53%) and higher (45.94%), respectively, in Sc when compared with Ip groups. Glucose and lactate values for ScS were the lowest (61.7% and 41.53%) compared to other groups. ScC glutamine value was the highest (40.8%) of all groups. Glutamate Sc values were (42.65%) lower than Ip groups. Sc groups showed greater survival time compared with Ip groups. ScS group showed 100% increase in survival time when compared with ScC. CONCLUSIONS: HMbeta supplementation can increase survival time and promotes metabolic changes in cancer-bearing animals, but it seems to work in a time-dependent manner.
Asunto(s)
Ácido 3-Hidroxibutírico/administración & dosificación , Composición Corporal/efectos de los fármacos , Carcinoma 256 de Walker/metabolismo , Metabolismo Energético/efectos de los fármacos , Glucógeno/metabolismo , Tejido Adiposo/metabolismo , Animales , Composición Corporal/fisiología , Caquexia/metabolismo , Caquexia/mortalidad , Caquexia/prevención & control , Carcinoma 256 de Walker/mortalidad , Suplementos Dietéticos , Modelos Animales de Enfermedad , Metabolismo Energético/fisiología , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Glucógeno Hepático/metabolismo , Masculino , Proteínas/metabolismo , Ratas , Ratas Wistar , Tasa de Supervivencia , Factores de TiempoRESUMEN
In this study we investigated the effect of lifelong supplementation of the diet with coconut oil (CO, rich in saturated fatty acids) or fish oil (FO, rich in n-3 polyunsaturated fatty acids, PUFAs) on tumor growth, animal survival, and metabolic indicators of cachexia in adult rats. Female Wistar rats were supplemented with CO or FO prior to mating and then throughout pregnancy and gestation, and then the male offspring were supplemented from weaning until 90 days of age. Then they were inoculated subcutaneously with Walker 256 tumor cells. Tumor weight at 14 days in control rats (those fed standard chow) was approximately 20 g. These animals displayed cancer cachexia, which was characterized by loss of weight, hypoglycemia, hyperlacticidemia, hypertriacylglycerolemia, and depletion of glycogen stores. Supplementation of the diet with CO did not change these parameters, except that there was a smaller decrease in serum triacylglycerol concentration. Supplementation of the diet with FO significantly decreased tumor growth (by approximately 60%), increased survival (50% at 30 days postinoculation vs. 30% in the controls and 13.5% in the CO group), and prevented the fall in body weight. Furthermore, FO supplementation partly abolished the fall in serum glucose, totally prevented the elevation in serum lactate concentrations, partly prevented the hypertriacylgylcerolemia, and preserved tissue glycogen stores. Lifelong consumption of FO, rich in n-3 PUFAs, protects against tumor growth and cancer cachexia and improves survival.
Asunto(s)
Caquexia/tratamiento farmacológico , Carcinoma 256 de Walker/tratamiento farmacológico , Suplementos Dietéticos , Ácidos Grasos Insaturados/uso terapéutico , Hipolipemiantes/uso terapéutico , Triglicéridos/uso terapéutico , Análisis de Varianza , Animales , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Caquexia/metabolismo , Caquexia/mortalidad , Carcinoma 256 de Walker/metabolismo , Carcinoma 256 de Walker/mortalidad , Ácidos Grasos Omega-3 , Ácidos Grasos Insaturados/administración & dosificación , Ácidos Grasos Insaturados/metabolismo , Femenino , Glucógeno/metabolismo , Hipolipemiantes/administración & dosificación , Hipolipemiantes/metabolismo , Ácido Láctico/sangre , Metabolismo de los Lípidos , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas , Ratas Wistar , Tasa de Supervivencia , Triglicéridos/administración & dosificación , Triglicéridos/metabolismoRESUMEN
It is commonly accepted that moderate intensity exercise is beneficial to the immune system. We tested the influence of a moderate intensity training protocol (8 weeks) upon immune system function in Wistar tumour-bearing (TB) rats. The metabolism of glucose and glutamine in lymphocytes and macrophages was assessed, together with some functional parameters (hydrogen peroxide production and lymphocyte proliferative response). These substrates were chosen since they represent the most important energetic and synthetic metabolites for these cellular types. The training protocol caused a decrease of 17.4 per cent in the production of H(2)O(2) by macrophages, as well as a decrease in glucose consumption (25 per cent) and lactate production (47.1 per cent), and an increase in the production of labelled CO(2) from the oxidation of [U-(14)C]-glucose, in TB rats. The training protocol was also able to induce changes in the maximal activity of some key enzymes in the metabolism of glucose and glutamine, a reduction of hexokinase (68.8 per cent) activity and an increase in the activity of citrate synthase (10.1 per cent) in TB rats. The training protocol increased the proliferative response of lymphocytes cultivated in the absence of mitogens (75 per cent), of those cultivated in the presence of ConA (38.2 per cent) and in the presence of LPS (45.0 per cent). These cells also showed an increase in the maximal activity of some key enzymes of the glycolytic and glutaminolytic pathways. Our data demonstrated that the training protocol was able to induce an increase in aerobic utilisation of both substrates in lymphocytes and macrophages. The training protocol was also able to prevent several changes in glucose and glutamine metabolism that are normally present in sedentary TB rats. These changes in immune cell metabolism induced by the training protocol were able to increase TB rat survival.
Asunto(s)
Caquexia/inmunología , Carcinoma 256 de Walker/inmunología , Linfocitos/metabolismo , Macrófagos/metabolismo , Condicionamiento Físico Animal , Animales , Caquexia/mortalidad , Caquexia/terapia , Carcinoma 256 de Walker/mortalidad , Carcinoma 256 de Walker/terapia , Glucosa/metabolismo , Glutamina/metabolismo , Peróxido de Hidrógeno/metabolismo , Lactatos/metabolismo , Activación de Linfocitos , Masculino , Fagocitosis , Ratas , Ratas WistarRESUMEN
In order to verify the effects of triiodothyronine (T3) administration in animals bearing Walker tumor, the authors have carried out an experimental study utilizing Wistar rats inoculated with both ascitic and solid Walker tumor, and Balb/c isogenic mice for the study of spreading of macrophages. The animals were treated with T3 20 micrograms/100 g of body weight and the data were analysed by Chi-square and Mann-Whitney tests. The authors conclude that T3 increases significantly the survival of rats bearing Walker tumor, and the spreading of macrophages when inoculated into the peritoneal cavity of mice. The hormone does not alter the weight of tumor mass. These results could be explained by the macrophageal activation and by the synthesis of the tumor necrosis factor.
Asunto(s)
Carcinoma 256 de Walker/tratamiento farmacológico , Triyodotironina Inversa/uso terapéutico , Animales , Carcinoma 256 de Walker/sangre , Carcinoma 256 de Walker/mortalidad , Femenino , Inyecciones Intraperitoneales , Activación de Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratas , Ratas Wistar , Triyodotironina Inversa/sangreRESUMEN
A inoculaçao de 37.10 5 células do tumor de Walker, por via intramuscular, na coxa do rato confirmou uma evoluçao rápida do mesmo, ao exibir um crescimento expansivo da massa tumoral no local do inóculo, culminando com a morte do animal. Todavia, quando da inoculaçao em ratos expostos previamente à "imunogenicidade destas células", observou-se uma evoluçao mais lenta e uma maior sobrevida, sugerindo modulaçao na imunidade destes animais. O contato prévio com as células tumorais ou ainda a fraca imunogenicidae destas células, provavelmente, possa ter sido suficiente e responsável pelo retardo no desenvolvimento do tumor e pela maior sobrevida dos animais