RESUMO
CONTEXT: Cancer Pain is considered a common and significant clinical problem in malignant neoplasms, comprising 20% to 50% of all patients with tumor progression. Laser photobiomodulation (L-PBM) has been used in a multitude of pain events, ranging from acute trauma to chronic articular. However, L-PBM has never been tested in cancer pain. OBJECTIVES: Evaluate hyperalgesia, edema, COX-1, COX-2, IL-10, and Bdkrb1 mRNA in low-level laser irradiated Walker-256 tumor-bearing rats. METHODS: Rat hind paw injected with Walker Tumor-256 (W-256) and divided into six groups of 6 rats: G1 (control) - W-256 injected, G2- W-256â¯+â¯Nimesulide, G3- W-256â¯+â¯1â¯J, G4- W-256â¯+â¯3â¯Jand G5- W256â¯+â¯6â¯J. Laser parameters: λâ¯=â¯660â¯nm, 3.57â¯W/cm2, Øâ¯=â¯0.028â¯cm2. Mechanical hyperalgesia was evaluated by Randall-Selitto test. Plethysmography measured edema; mRNA levels of COX-1, COX-2, IL-10, and Bdkrb1were analyzed. RESULTS: It was found that the W-256â¯+â¯1â¯J group showed a decrease in paw edema, a significant reduction in pain threshold. Higher levels of IL-10 and lower levels of COX-2 and Bdkrb1 were observed. CONCLUSION: Results suggest that 1â¯Jâ¯L-PBM reduced the expression of COX-2 and Bdkrb1 and increasing IL-10 gene expression, promoting analgesia to close levels to nimesulide.
Assuntos
Hiperalgesia/radioterapia , Lasers Semicondutores/uso terapêutico , Terapia com Luz de Baixa Intensidade , Animais , Carcinoma 256 de Walker/metabolismo , Carcinoma 256 de Walker/patologia , Linhagem Celular Tumoral , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Edema/metabolismo , Edema/patologia , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Masculino , Pletismografia , Ratos , Ratos Wistar , Transplante HeterólogoRESUMO
AIMS: Cancer is a multifactorial disease characterized by an uncontrolled growth of cells that can lead to cachexia-anorexia syndrome. Botryosphaeran, a fungal (1 â 3)(1 â 6)-ß-D-glucan produced by Botryosphaeria rhodina MAMB-05, has presented antimutagenic, antiproliferative, pro-apoptotic, hypoglycemic and hypocholesterolemic effects. This study evaluated the effects of botryosphaeran (30 mg/kg b.w./day) on tumor development and cachexia syndrome in Walker-256 tumor-bearing rats, and also the metabolic and hematological profiles of these animals. MATERIALS AND METHODS: Male Wistar rats were divided into 3 groups: control (C), control tumor (CT) and control tumor botryosphaeran (CTB). On the first day, 1 × 107 Walker-256 tumor cells were inoculated subcutaneously into the right flank of the CT and CTB rats, and concomitantly treatment with botryosphaeran (30 mg/kg b.w./day) started. After the 15th day of treatment, biological parameters, tumor development, cachexia, glucose and lipid profiles, hemogram and protein expression were analyzed. KEY FINDINGS: Botryosphaeran significantly reduced tumor development (p = 0.0024) and cancer cachexia, modulated the levels of glucose, triglycerides and HDL-cholesterol, and corrected macrocytic anemia. Botryosphaeran also increased significantly the bax expression in the tumor tissue (p = 0.038) demonstrating that this (1 â 3)(1 â 6)-ß-D-glucan is increasing the apoptosis of tumor cells. p53, p27, bcl-2, caspase-3 and Forkhead transcription factor 3a (FOXO3a) protein expression were similar among the groups. SIGNIFICANCE: This study demonstrated that botryosphaeran was effective in decreasing tumor development and cachexia by direct and indirect mechanisms increasing apoptosis and improving the metabolic and hematological profiles.
Assuntos
Apoptose/efeitos dos fármacos , Caquexia/tratamento farmacológico , Carcinoma 256 de Walker/tratamento farmacológico , Glucanos/administração & dosagem , Animais , Caquexia/etiologia , Carcinoma 256 de Walker/patologia , Glucanos/farmacologia , Glucose/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Euphorbia tirucalli L. is an African plant that grows well in Brazil. Individuals diagnosed with cancer frequently consume latex from E. tirucalli, dissolved in drinking water. In vitro studies confirm the antitumor potential of E. tirucalli latex, but in vivo evaluations are scarce. AIM OF THE STUDY: To evaluate the effect of intake of an aqueous solution of E. tirucalli latex on tumor growth, cachexia, and immune response in Walker 256 tumor-bearing rats. MATERIALS AND METHODS: Latex from E. tirucalli was collected and analyzed by LC-MS. Sixty male Wistar rats (age, 90 days) were randomly divided into four groups: C, control group (without tumor); W, Walker 256 tumor-bearing group; SW1, W animals but treated with 25⯵L latex/mL water; and SW2, W animals but treated with 50⯵L latex/mL water. Animals received 1â¯mL of latex solution once a day by gavage. After 15â¯d, animals were euthanized, tumor mass was determined, and glucose and triacylglycerol serum levels were measured by using commercial kits. Change in the body weight during tumor development was calculated, and proliferation capacity of tumor cells was assessed by the Alamar Blue assay. Phagocytosis and superoxide anion production by peritoneal macrophages and circulating neutrophils were analyzed by enzymatic and colorimetric assays. Data are analyzed by one-way ANOVA followed by Tukey's post-hoc test, with the significance level set at 5%. RESULTS: The analysis of the latex revealed the presence of triterpenes. The ingestion of the latex aqueous solution promoted 40% and 60% reduction of the tumor mass in SW1 and SW2 groups, respectively (pâ¯<â¯0.05). The proliferative capacity of tumor cells from SW2 group was 76% lower than that of cells from W group (pâ¯<â¯0.0001). Animals treated with latex gained, on average, 20â¯g (SW1) and 8â¯g (SW2) weight. Glucose and triacylglycerol serum levels in SW1 and SW2 animals were similar to those in C group rats. Peritoneal macrophages and blood neutrophils from SW1 and SW2 animals produced 30-40% less superoxide anions than those from W group animals (pâ¯<â¯0.05), but neutrophils from SW2 group showed an increased phagocytic capacity (20%, vs. W group). CONCLUSIONS: E. tirucalli latex, administered orally for 15â¯d, efficiently reduced tumor growth and cachexia in Walker 256 tumor-bearing rats. Decreased tumor cell proliferative capacity was one of the mechanisms involved in this effect. Further, the data suggest immunomodulatory properties of E. tirucalli latex. The results agree with folk data on the antitumor effect of latex ingestion, indicating that it may be useful as an adjunct in the treatment of cancer patients. For this, further in vivo studies in animal and human models need to be conducted.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Caquexia/prevenção & controle , Carcinoma 256 de Walker/tratamento farmacológico , Euphorbia , Látex/farmacologia , Extratos Vegetais/farmacologia , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Caquexia/sangue , Caquexia/imunologia , Caquexia/fisiopatologia , Carcinoma 256 de Walker/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Euphorbia/química , Látex/isolamento & purificação , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Extratos Vegetais/isolamento & purificação , Ratos Wistar , Triglicerídeos/sangue , Carga Tumoral/efeitos dos fármacos , Redução de Peso/efeitos dos fármacosRESUMO
Cancer-bearing often exhibits hypoinsulinemia, insulin (INS) resistance and glutamine depletion associated with cachexia. However, INS and glutamine effects on cachexia metabolic abnormalities, particularly on tumor-affected proteins related to INS resistance, are poorly known. The main purpose of this study was to investigate the effects of INS and glutamine dipeptide (GDP) treatments on phospho-protein kinase B (p-Akt), and phospho-hormone sensitive lipase (p-HSL) in Walker-256 tumor-bearing rats. INS (NPH, 40 UI/kg, subcutaneous), GDP (1.5 g/kg, oral), INS+GDP or vehicle (control rats) were administered for 13 days, once a day, starting at the day of inoculation of tumor cells. The experiments were performed 4 hours after the last treatment to evaluate acute effects of INS and GDP, besides the chronic effects. INS and/or INS+GDP treatments, which markedly increased the insulinemia, increased the p-Akt: total Akt ratio and prevented the increased p-HSLSer552 : total HSL ratio in the retroperitoneal fat of tumor-bearing rats, without changing the INS resistance and increased expression of factor tumor necrosis-α (TNF-α) in this tissue. INS and INS+GDP also increased the p-Akt: total Akt ratio, whereas GDP and INS+GDP increased the GLUT4 glucose transporter gene expression, in the gastrocnemius muscle of the tumor-bearing rats. Accordingly, treatments with INS and INS+GDP markedly reduced glycemia, increased retroperitoneal fat and attenuated the body mass loss of tumor-bearing rats. In conclusion, hyperinsulinemia induced by high-dose INS treatments increased Akt phosphorylation and prevented increased p-HSLSer552 : total HSL ratio, overlapping INS resistance. These effects are consistent with increased fat mass gain and weight loss (cachexia) attenuation of tumor-bearing rats, evidencing that Akt activation is a potential strategy to prevent loss of fat mass in cancer cachexia.
Assuntos
Caquexia/tratamento farmacológico , Carcinoma 256 de Walker/complicações , Glutamina/farmacologia , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Glicemia/análise , Caquexia/etiologia , Caquexia/metabolismo , Caquexia/patologia , Carcinoma 256 de Walker/patologia , Quimioterapia Combinada , Resistência à Insulina , Masculino , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos WistarRESUMO
Leucine can stimulate protein synthesis in skeletal muscle, and recent studies have shown an increase in leucine-related mitochondrial biogenesis and oxidative phosphorylation capacity in muscle cells. However, leucine-related effects in tumour tissues are still poorly understood. Thus, we described the effects of leucine in both in vivo and in vitro models of a Walker-256 tumour. Tumour-bearing Wistar rats were randomly distributed into a control group (W; normoprotein diet) and leucine group (LW; leucine-rich diet [normoprotein + 3% leucine]). After 20 days of tumour evolution, the animals underwent 18-fludeoxyglucose positron emission computed tomography (18F-FDG PET-CT) imaging, and after euthanasia, fresh tumour biopsy samples were taken for oxygen consumption rate measurements (Oroboros Oxygraph), electron microscopy analysis and RNA and protein extraction. Our main results from the LW group showed no tumour size change, lower tumour glucose (18F-FDG) uptake, and reduced metastatic sites. Furthermore, leucine stimulated a shift in tumour metabolism from glycolytic towards oxidative phosphorylation, higher mRNA and protein expression of oxidative phosphorylation components, and enhanced mitochondrial density/area even though the leucine-treated tumour had a higher number of apoptotic nuclei with increased oxidative stress. In summary, a leucine-rich diet directed Walker-256 tumour metabolism to a less glycolytic phenotype profile in which these metabolic alterations were associated with a decrease in tumour aggressiveness and reduction in the number of metastatic sites in rats fed a diet supplemented with this branched-chain amino acid.
Assuntos
Carcinoma 256 de Walker/metabolismo , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Leucina/farmacologia , Fosforilação Oxidativa/efeitos dos fármacos , Animais , Carcinoma 256 de Walker/dietoterapia , Carcinoma 256 de Walker/patologia , Feminino , Alimentos Formulados , Metástase Neoplásica , Ratos , Ratos WistarRESUMO
KEY POINTS: Cancer growth, cell proliferation and cachexia index can be attenuated by the beneficial programming effect of moderate exercise training, especially if it begins in adolescence. Walker 256 tumour-bearing rats who started exercise training during adolescence did not revert the basal low glycaemia and insulinaemia observed before tumour cell inoculation. The moderate exercise training improved glucose tolerance and peripheral insulin sensitivity only in rats exercised early in adolescence. The chronic effects of our exercise protocol are be beneficial to prevent cancer cachexia and hold clear potential as a nonpharmacological therapy of insulin sensitization. ABSTRACT: We tested the hypothesis that moderate exercise training, performed early, starting during adolescence or later in life during adulthood, can inhibit tumour cell growth as a result of changes in biometric and metabolic markers. Male rats that were 30 and 70 days old performed a treadmill running protocol over 8 weeks for 3 days week-1 , 44 min day-1 and at 55-65% VÌO2max . After the end of training, a batch of rats was inoculated with Walker 256 carcinoma cells. At 15 days after carcinoma cell inoculation, the tumour was weighed and certain metabolic parameters were evaluated. The data demonstrated that physical performance was better in rats that started exercise training during adolescence according to the final workload and VÌO2max . Early or later moderate exercise training decreased the cachexia index, cell proliferation and tumour growth; however, the effects were more pronounced in rats that exercised during adolescence. Low glycaemia, insulinaemia and tissue insulin sensitivity was not reverted in Walker 256 tumour-bearing rats who trained during adolescence. Cancer growth can be attenuated by the beneficial programming effect of moderate exercise training, especially if it begins during adolescence. In addition, improvement in glucose-insulin homeostasis might be involved in this process.
Assuntos
Carcinoma 256 de Walker/terapia , Condicionamento Físico Animal/métodos , Animais , Caquexia/metabolismo , Caquexia/prevenção & controle , Carcinoma 256 de Walker/patologia , Carcinoma 256 de Walker/prevenção & controle , Células Cultivadas , Glucose/metabolismo , Resistência à Insulina , Masculino , Ratos , Ratos WistarRESUMO
BACKGROUND: The exact signalling mechanism of the mTOR complex remains a subject of constant debate, even with some evidence that amino acids participate in the same pathway as used for insulin signalling during protein synthesis. Therefore, this work conducted further study of the actions of amino acids, especially leucine, in vivo, in an experimental model of cachexia. We analysed the effects of a leucine-rich diet on the signalling pathway of protein synthesis in muscle during a tumour growth time-course. METHODS: Wistar rats were distributed into groups based on Walker-256 tumour implant and subjected to a leucine-rich diet and euthanised at three different time points following tumour development (the 7th, 14th and 21st day). We assessed the mTOR pathway key-proteins in gastrocnemius muscle, such as RAG-A-GTPase, ERK/MAP4K3, PKB/Akt, mTOR, p70S6K1, Jnk, IRS-1, STAT3, and STAT6 comparing among the experimental groups. Serum WF (proteolysis-induced factor like from Walker-256 tumour) and muscle protein synthesis and degradation were assessed. RESULTS: The tumour-bearing group had increased serum WF content, and the skeletal-muscle showed a reduction in IRS-1 and RAG activation, increased PKB/Akt and Erk/MAP4K3 on the 21st day, and maintenance of p70S6K1, associated with increases in muscle STAT-3 and STAT-6 levels in these tumour-bearing rats. CONCLUSION: Meanwhile, the leucine-rich diet modulated key steps of the mTOR pathway by triggering the increased activation of RAG and mTOR and maintaining JNK, STAT-3 and STAT-6 levels in muscle, leading to an increased muscle protein synthesis, reducing the degradation during tumour evolution in a host, minimising the cancer-induced damages in the cachectic state.
Assuntos
Caquexia/prevenção & controle , Carcinoma 256 de Walker/dietoterapia , Suplementos Nutricionais , Leucina/administração & dosagem , Serina-Treonina Quinases TOR/metabolismo , Animais , Caquexia/etiologia , Carcinoma 256 de Walker/complicações , Carcinoma 256 de Walker/patologia , Feminino , Proteínas Musculares/biossíntese , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Proteólise/efeitos dos fármacos , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
Capsaicin (trans-8-methyl-n-vanillyl-6-nonenamide) is the main pungent component found in hot peppers. AIM: In this study, we investigated the effect of capsaicin treatment on tumor growth and the metabolic indicators of cachexia in Walker 256 tumor-bearing rats. METHODS: Male Wistar rats were inoculated subcutaneously in the right flank with 1 ml of a sterile suspension of 3 × 107 Walker tumor cells. The treated groups received capsaicin intraperitoneal 5 mg/kg body weight for 13 days. RESULTS: The tumor weight on Day 14 in the non-treated group was 18 g. The rats also had a body weight loss, hypoglycemia, hyperlactacidemia, hypertriacylglycerolemia, and a depletion in glycogen storage. Treatment with capsaicin decreased tumor growth by 49% and a reversal of triacylglycerol serum. We also found a 32% reduction in tumor cell proliferation ex vivo. Lactate serum concentrations and body weight were lower but did not reach control levels. CONCLUSION: The treatment with capsaicin reduces tumor growth and cellular proliferation along with increased apoptosis and partial cachexia reversal.
Assuntos
Caquexia/tratamento farmacológico , Capsaicina/uso terapêutico , Carcinoma 256 de Walker/tratamento farmacológico , Animais , Carcinoma 256 de Walker/patologia , Proliferação de Células/efeitos dos fármacos , Ácido Láctico/sangue , Masculino , Ratos , Ratos Wistar , Canais de Cátion TRPV/fisiologia , Triglicerídeos/sangueRESUMO
Chia seed (Salvia hispanica L.) contains high amounts of n-3 α-linolenic acid (ALA) and has been associated with many health benefits. The aim of the present study was to evaluate the AIN-93 diet supplemented by chia flour on cancer-cachexia development and tissues inflammatory response. Wistar rats at 30 days old were treated with control diet or diet supplemented with chia flour for eight weeks. After this period, half of the animals in each diet group were inoculated with Walker 256 tumor cells. On the 14th day after tumor inoculation, the animals were euthanized and white adipose tissue depots, liver, gastrocnemius muscle, and tumor were removed. The tumor weight was higher and IL-10 content was lower in chia flour group. The tumor bearing did not modify the cytokines content in gastrocnemius muscle, retroperitoneal and epididymal adipose tissue, however, it decreased IL-1ß and TNF-α content in liver, and IL6R and IL-10R protein content in mesenteric adipose tissue. In conclusion, our results demonstrated that supplementation with chia flour did not prevent the tumor bearing effects in Walker 256 model.
Assuntos
Carcinoma 256 de Walker/patologia , Suplementos Nutricionais , Inflamação/metabolismo , Salvia , Tecido Adiposo/metabolismo , Animais , Peso Corporal , Carcinoma 256 de Walker/dietoterapia , Citocinas/metabolismo , Farinha/análise , Teste de Tolerância a Glucose , Inflamação/dietoterapia , Lipídeos/análise , Masculino , Transplante de Neoplasias , Tamanho do Órgão , Proteínas/análise , Ratos WistarRESUMO
This study was designed to appraise the relationship between enteric neuropathy and oxidative stress in cancer cachexia under l-glutamine-supplemented diet. Total and nitrergic neuronal populations were investigated in jejunum and ileum in four experimental groups: control (C); control l-glutamine-supplemented diet (CG); Walker-256 tumor (TW); and Walker-256 tumor supplemented with l-glutamine (TWG). In addition, local oxidative stress, neuronal nitric oxide synthase (nNOS) enzyme and nitric oxide (NO) levels were evaluated. Neuronal density and somatic area of the total and nitrergic populations were reduced in TW rats, which was accompanied by high oxidative stress, NO and nNOS levels. l-glutamine supplementation prevented neuronal atrophy, changes in pan neuronal density and nNOS overexpression (ileum), and restored total antioxidant capacity. Nevertheless, the oxidative stress was partially mitigated and no effect was observed on the reduction of nitrergic population and NO levels. l-glutamine-supplemented diet extenuates NO-mediated damage on the myenteric plexus although has a small benefit on oxidative stress.