RESUMEN
AIMS: Doxorubicin is a prominent anticancer agent. However, its organotoxic potential has restricted its clinical use. The current study was performed to investigate the protective effect of pirfenidone and vitamin D against doxorubicin-triggered nephrotoxicity. MATERIALS AND METHODS: Female albino mice (5 mice per group) were inoculated with Ehrlish scites carcinoma (EAC) cells for induction of solid tumor and treated with pirfenidone 500 mg/kg orally (p.o.) or vitamin D 0.5 µg/kg intraperitonially (i.p.), either individually or combined with single doxorubicin (15 mg/kg; i.p.) dose. Additionally, 5 mice were served as a normal group. Treatment commenced 7 days after inoculation of Ehrlich ascites carcinoma cells and lasted for 14 days. KEY FINDINGS: Pirfenidone and vitamin D enhanced the anti-tumor activity of doxorubicin, by decreasing tumor weight and volume. Doxorubicin increased kidney weights, creatinine, urea levels and collagen fibers deposition within renal tubules. Moreover, doxorubicin was associated with overexpression of nuclear factor-kappa B (NF-κB) and alpha-smooth muscle actin (α-SMA) as both parameters assessed by kidney immunohistochemistry. Furthermore, histological signs of large areas of interistital fibrosis and cellular infiltration were significant with sole doxorubicin treatment. Notably, doxorubicin elevated both MCP1 and TGFB1 gene expression in addition to increasing the protein expression of Smad3 and Jun N-terminal Kinase-1 (JNK1) while decreasing that of Smad7. Pirfenidone in combined with vitamin D abolished doxorubicin-evoked disturbances in the aforementioned parameters and blunted all histological alterations. SIGNIFICANCE: Pirfenidone and vitamin D demonstrated a viable approach to suppress the nephrotoxicity initiated by doxorubicin through inhibiting the JNK1 and MCP-1 pathways.
Asunto(s)
Carcinoma de Ehrlich/complicaciones , Doxorrubicina/toxicidad , Fibrosis/prevención & control , Enfermedades Renales/prevención & control , Piridonas/farmacología , Vitamina D/farmacología , Animales , Antibióticos Antineoplásicos/toxicidad , Antineoplásicos/farmacología , Femenino , Fibrosis/etiología , Fibrosis/patología , Enfermedades Renales/etiología , Enfermedades Renales/patología , Ratones , Vitaminas/farmacologíaRESUMEN
It has been widely reported that cancer, along with its treatment regimens, cause severe toxicity in the host. A suitable agent having chemopreventive properties as well as capabilities of ameliorating tumor- and drug-induced toxicities is of imminent need. Pomegranate has been projected as an excellent anti-tumor, anti-inflammatory and anti-oxidant agent. In this study, for the first time, we delineated the exact signaling cascade by which dietary supplementation of pomegranate fruit extract (PFE) protects tumor-bearing mice from tumor-induced hepatotoxicity. Increased activities of serum Alanine transaminase, Aspartate transaminase, Lactate dehydrogenase and Alkaline phosphatase, as well as histological studies confirmed the establishment of a state of hepatic dysfunction in tumor-bearers. Further investigations revealed that increased hepatic reactive oxygen species content and glutathione depletion-initiated apoptosis in these hepatocytes as we observed an alteration in the apoptotic proteins. PFE supplementation in tumor-bearing mice, on the other hand, differentially modulated redox-sensitive transcription factors Nrf2 and NF-κB, ultimately decreasing tumor-induced hepatic oxidative damage and cell death. siRNA-mediated inhibition of Nrf2 and NF-κB completely abolished the hepato-protective activities of PFE while pre-treatment of tumor-conditioned hepatocytes with N-acetyl cysteine augmented the cyto-protective properties of PFE. The present study clearly identified Nrf2/NF-κB/glutathione axis as the key factor behind the hepatoprotective potential of PFE. These findings would add to the existing knowledge about cancer chemoprevention by dietary polyphenols and might lead to the application of pomegranate polyphenols as supplement to escalate the effectiveness of cancer therapy by protecting normal cells from cancer related toxicities.
Asunto(s)
Carcinoma de Ehrlich/complicaciones , Glutatión/metabolismo , Hepatopatías/prevención & control , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Polifenoles/administración & dosificación , Granada (Fruta) , Animales , Antioxidantes/metabolismo , Carcinoma de Ehrlich/metabolismo , Citocinas/metabolismo , Suplementos Dietéticos , Femenino , Hepatocitos/fisiología , Inflamación , Hígado/metabolismo , Hepatopatías/etiología , Hepatopatías/metabolismo , Hepatopatías/patología , Ratones , Estrés Oxidativo , Extractos Vegetales/administración & dosificaciónRESUMEN
BACKGROUND: Cancer is a multifactorial disease caused by uncontrolled proliferation of cells. About 50-80% of cancer patients develop cachexia, a complex metabolic syndrome associated with an increase of mortality and morbidity. However, there are no effective therapies in medical clinic for cancer cachexia. Vochysia tucanorum Mart. is a common three of the Brazilian "Cerrado". The butanolic fraction of V. tucanorum (Fr-BuVt), very rich in triterpenes with various biological activities, might be interesting in being tested in cancer cachexia syndrome. Hence, the present study was undertaken to investigate the antitumoral activity of Fr-BuVt and its potential against cachexia development. METHODS: Ehrlich tumor was used as model of cancer cachexia. Ascitic Ehrlich tumor cells were collected, processed and inoculated subcutaneously in saline solution (1 × 107/100 µl; ≥95% viability) for the obtention of solid Ehrlich carcinoma. After inoculation, solid Ehrlich carcinoma-bearing mice were treated by 14 consecutive days by gavage with Fr-BuVt (200 mg/kg). Body weight and tumor volume were measure during the treatment period. Tumors were removed, weighed and properly processed to measure the content and phosphorylation levels of key-proteins involved to apoptotic and proliferation process by Western Blot. Muscles and adipose tissues were removed for weighed. Serum was collected to cytokines levels and energetic blood markers measurements. RESULTS: The treatment with the Fr-BuVt (200 mg/kg, 14 days) decreased the solid Ehrlich tumor volume and weight besides increased the expression of the pro-apoptotic proteins caspase-3 and BAX, but also decreased the expression of the proteins involved in proliferation NFκB, mTOR and ERK. In addition, our data shows that the administration of Fr-BuVt was able to prevent the installation of cancer cachexia in Ehrlich carcinoma-bearing mice, since prevented the loss of body weight, as well as the loss of muscle and adipose tissue. Moreover, an improvement in some blood parameters such as decrease in cytokines TNF-α and IL-6 levels is observed. CONCLUSIONS: The study revealed that Fr-BuVt has antitumoral activity and prevent installation of cancer cachexia in Ehrlich model. Therefore, Fr-BuVt may represent an alternative treatment for cancer cachexia.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Caquexia/prevención & control , Carcinoma de Ehrlich/tratamiento farmacológico , Myrtales/química , Extractos Vegetales/farmacología , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Brasil , Butanoles , Caquexia/etiología , Carcinoma de Ehrlich/complicaciones , Proliferación Celular/efectos de los fármacos , Citocinas/sangre , Masculino , Ratones , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cardiomyopathy is one of the characteristic features of cancer. In this study, we establish a suitable model to study breast cancer-induced cardiomyopathy in mice. We used Ehrlich Ascites Carcinoma cells to induce subcutaneous tumor in 129/SvJ mice and studied its effect on heart function. In Ehrlich Ascites Carcinoma bearing mice, we found significant reduction in left ventricle wall thickness, ejection fraction, and fractional shortening increase in left ventricle internal diameter. We found higher muscle atrophy, degeneration, fibrosis, expression of cell-adhesion molecules and cell death in tumor-bearing mice hearts. As observed in cancer patients, we found that mTOR, a key signalling molecule responsible for maintaining cell growth and autophagy was suppressed in this model. Tumor bearing mice hearts show increased expression and nuclear localization of TFEB and FoxO3a transcription factors, which are involved in the upregulation of muscle atrophy genes, lysosomal biogenesis genes and autophagy genes. We propose that Ehrlich Ascites Carcinoma induced tumor can be used as a model to identify potential therapeutic targets for the treatment of heart failure in patients suffering from cancer-induced cardiomyopathy. This model can also be used to test the adverse consequences of cancer chemotherapy in heart.
Asunto(s)
Carcinoma de Ehrlich/patología , Cardiomiopatías/patología , Animales , Autofagia , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Beclina-1/genética , Beclina-1/metabolismo , Caquexia/etiología , Caquexia/patología , Carcinoma de Ehrlich/complicaciones , Carcinoma de Ehrlich/metabolismo , Cardiomiopatías/etiología , Modelos Animales de Enfermedad , Fibrosis , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Lisosomas/metabolismo , Ratones , Ratones de la Cepa 129 , Miocardio/metabolismo , Miocardio/patología , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Diabetes has been listed as a risk factor for various types of cancer. Cancer cell development can be promoted by increased levels of IGF-1 and hyperinsulinemia that are associated with diabetes type II. Metformin is an anti-diabetic agent and its potential antitumor impact has become the objective of numerous studies. In this vein, we hypothesize that using metformin in diabetes type II mice may synergistic with carboplatin for reducing the risk of cancer. Therefore, the study aimed to evaluate the in vivo antitumor activity of metformin against solid EAC tumor growth in female diabetic mice and its potential pro-apoptotic and anti-proliferative effects with clarification of its inconclusive biological mechanisms. Mice were assigned into nine groups; normal control, diabetic control, diabetic plus EAC control, EAC control, and treated groups received carboplatin and/or metformin (100, 200mg/kg). Metformin administration especially with high dose potentiated the antitumor activity of carboplatin displayed by increased pro-apoptotic activators "caspase-3 and bax" and reduced anti-apoptotic protein bcl-2. This was confirmed by the histopathological scores. Moreover, the combination therapy was effective in attenuating the expression of the pro-angiogenic mediator "VEGF" and the microvessel density as revealed by the CD34. Additionally, this combination down-regulated the high levels of the mutagenic element "IGF-1" and its receptor expression, and attenuated the intensity of inflammatory mediators. In conclusion, it was found that metformin therapy could enhance apoptotic marker, and suppress the neovascularization and proliferation process. This clarified the ability of metformin to support carboplatin activity in reducing tumor progression in type II diabetes.
Asunto(s)
Antineoplásicos/uso terapéutico , Carboplatino/uso terapéutico , Carcinoma de Ehrlich/tratamiento farmacológico , Diabetes Mellitus Experimental/tratamiento farmacológico , Factor I del Crecimiento Similar a la Insulina/metabolismo , Metformina/uso terapéutico , Neovascularización Patológica/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Carcinoma de Ehrlich/complicaciones , Caspasa 3/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diabetes Mellitus Experimental/complicaciones , Sinergismo Farmacológico , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Ratones , Ratones Endogámicos , Neovascularización Patológica/complicaciones , Receptor IGF Tipo 1/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Cancer pain directly affects the patient's quality of life. We have previously demonstrated that the subcutaneous administration of the mammary adenocarcinoma known as Ehrlich tumor induces pain in mice. Several studies have shown that the flavonoid quercetin presents important biological effects, including anti-inflammatory, antioxidant, analgesic, and antitumor activity. Therefore, the analgesic effect and mechanisms of quercetin were evaluated in Ehrlich tumor-induced cancer pain in mice. Intraperitoneal (i.p.) treatments with quercetin reduced Ehrlich tumor-induced mechanical and thermal hyperalgesia, but not paw thickness or histological alterations, indicating an analgesic effect without affecting tumor growth. Regarding the analgesic mechanisms of quercetin, it inhibited the production of hyperalgesic cytokines IL-1ß and TNFα and decreased neutrophil recruitment (myeloperoxidase activity) and oxidative stress. Naloxone (opioid receptor antagonist) inhibited quercetin analgesia without interfering with neutrophil recruitment, cytokine production, and oxidative stress. Importantly, cotreatment with morphine and quercetin at doses that were ineffective as single treatment reduced the nociceptive responses. Concluding, quercetin reduces the Ehrlich tumor-induced cancer pain by reducing the production of hyperalgesic cytokines, neutrophil recruitment, and oxidative stress as well as by activating an opioid-dependent analgesic pathway and potentiation of morphine analgesia. Thus, quercetin treatment seems a suitable therapeutic approach for cancer pain that merits further investigation.
Asunto(s)
Carcinoma de Ehrlich/complicaciones , Dolor/tratamiento farmacológico , Dolor/etiología , Quercetina/uso terapéutico , Analgésicos/farmacología , Analgésicos/uso terapéutico , Analgésicos Opioides/farmacología , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Interleucina-1beta/biosíntesis , Masculino , Ratones , Morfina/farmacología , Morfina/uso terapéutico , Naloxona/farmacología , Naloxona/uso terapéutico , Infiltración Neutrófila/efectos de los fármacos , Estrés Oxidativo , Dolor/patología , Quercetina/farmacología , Piel/patología , Médula Espinal/patología , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Multiple injections of conotoxin MII, a blocker of alfa3-ß2 and alfa6-containing subtypes of nicotinic acetylcholine receptors (n-AChRs), as well as conotoxin ArIB11L16D, a blocker of alfa7 subtype n-AChR, at a dose of 1 nmol/kg reduce both the lactate dehydrogenase level in tumor cells and the inflammatory leukocyte infiltration in tumor tissue in mice bearing Ehrlich carcinoma. The first stage of pathomorphism was detected in the tumor tissue after the treatment with the ArIB11L16D conotoxin, whereas the second stage was observed after the treatment with conotoxins RgIA and MII. Only MII injections led to a significant reduction in tumor growth. Our results show the involvement of n-AChRs in the regulation of metabolic processes and cell-cell interactions related to carcinogenesis and tumor-associated inflammation.
Asunto(s)
Carcinogénesis/efectos de los fármacos , Carcinoma de Ehrlich/metabolismo , Carcinoma de Ehrlich/patología , Conotoxinas/farmacología , Antagonistas Nicotínicos/farmacología , Receptores Nicotínicos/metabolismo , Animales , Carcinoma de Ehrlich/complicaciones , Inflamación/complicaciones , Inflamación/metabolismo , RatonesRESUMEN
OBJECTIVE: Once administered intravenously, technetium-99m (99mTc)-labeled phytate binds to calcium in the serum and behaves as a nanoparticle. On the basis of the high permeability of the tumor vasculature, 99mTc-phytate is expected to leak and accumulate specifically in inflammatory cells. The aim of this study was to evaluate the potential of 99mTc-phytate in assessing the degree of inflammation in Ehrlich solid tumors in mice. MATERIALS AND METHODS: 99mTc-phytate was prepared by adding pertechnetate to a solution containing phytic acid and stannous chloride. The blood half-life of this particle following intravenous injection was determined using blood samples from healthy animals, whereas its size was measured by photon correlation spectroscopy. Scintigraphic imaging and biodistribution studies were carried out in tumor-bearing mice at 30 min and 2 h after injection. RESULTS: The average size of the particles was in the range of 200 nm, suggesting that they are capable of passively passing through fenestrations in tumor vessels, which are 200-2000 nm in size. The blood half-life for 99mTc-phytate was found to be 2.1 min, a result that is in agreement with previous studies. Data from tumor-bearing mice showed high tumor uptake at 2 h after 99mTc-phytate administration. As a result, a high tumor-to-muscle ratio was achieved (T/M = 25.9 ± 7.54). CONCLUSION: These findings indicate that 99mTc-sodium phytate has promising properties for identifying the type of tumor. This approach will have significant implications for characterizing tumor biology and treatment of malignant lesions.
Asunto(s)
Carcinoma de Ehrlich/diagnóstico por imagen , Ácido Fítico/química , Tecnecio/química , Animales , Carcinoma de Ehrlich/complicaciones , Inflamación/complicaciones , Inflamación/diagnóstico por imagen , Ratones , Tamaño de la Partícula , Ácido Fítico/farmacocinética , Radioquímica , Cintigrafía , Distribución TisularRESUMEN
The Ehrlich tumor is a mammary adenocarcinoma of mice that can be developed in solid and ascitic forms depending on its administration in tissues or cavities, respectively. The present study investigates whether the subcutaneous plantar administration of the Ehrlich tumor cells induces pain-like behavior and initial pharmacological susceptibility characteristics. The Ehrlich tumor cells (1 × 10(4)-10(7) cells) induced dose-dependent mechanical hyperalgesia (electronic version of the von Frey filaments), paw edema/tumor growth (caliper), and flinches compared with the saline group between days 2 and 12. There was no difference between doses of cells regarding thermal hyperalgesia in the hot-plate test. Indomethacin (a cyclooxygenase inhibitor) and amitriptyline hydrochloride (a tricyclic antidepressant) treatments did not affect flinches or thermal and mechanical hyperalgesia. On the other hand, morphine (an opioid) inhibited the flinch behavior and the thermal and mechanical hyperalgesia. These effects of morphine on pain-like behavior were prevented by naloxone (an opioid receptor antagonist) treatment. None of the treatments affected paw edema/tumor growth. The results showed that, in addition to tumor growth, administration of the Ehrlich tumor cells may represent a novel model for the study of cancer pain, specially the pain that is susceptible to treatment with opioids, but not to cyclooxygenase inhibitor or to tricyclic antidepressant.
Asunto(s)
Conducta Animal , Carcinoma de Ehrlich/tratamiento farmacológico , Carcinoma de Ehrlich/fisiopatología , Evaluación Preclínica de Medicamentos , Dolor/tratamiento farmacológico , Dolor/fisiopatología , Amitriptilina/farmacología , Amitriptilina/uso terapéutico , Animales , Conducta Animal/efectos de los fármacos , Carcinoma de Ehrlich/complicaciones , Carcinoma de Ehrlich/patología , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Edema/complicaciones , Edema/tratamiento farmacológico , Edema/patología , Hiperalgesia/patología , Hiperalgesia/fisiopatología , Indometacina/farmacología , Indometacina/uso terapéutico , Masculino , Ratones , Morfina/farmacología , Morfina/uso terapéutico , Trasplante de Neoplasias , Nocicepción/efectos de los fármacos , Dolor/etiología , Tejido Subcutáneo/patología , TemperaturaRESUMEN
To better understand the interactions between opportunistic fungi and their hosts, we investigated hydrogen peroxide (H2O2), nitric oxide and TNF-alpha production by peritoneal macrophages from Ehrlich tumour-bearing mice (TBM) during microbial infections. For this purpose, TBM at days 7, 14 and 21 of tumour progression were inoculated intraperitoneally with C. albicans and evaluated after 24 and 72 h. We observed that TBM showed significant increases in H2O2, TNF-alpha levels and fungal clearance at day 7 after C. albicans infection. However, as the tumour advanced, there was a progressive decline in the release of H2O2 and TNF-alpha that was paired with the dissemination of C. albicans. These results demonstrate that protective macrophage activities against Candida albicans are limited to the initial stages of tumour growth; continued solid tumour growth weakened the macrophage response and as a consequence, weakened the host's susceptibility to opportunistic infections.
Asunto(s)
Candidiasis/complicaciones , Candidiasis/inmunología , Carcinoma de Ehrlich/complicaciones , Carcinoma de Ehrlich/inmunología , Macrófagos Peritoneales/inmunología , Infecciones Oportunistas/complicaciones , Animales , Candida albicans , Peróxido de Hidrógeno/metabolismo , Macrófagos Peritoneales/metabolismo , Masculino , Ratones , Óxido Nítrico/biosíntesis , Infecciones Oportunistas/inmunología , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
To better understand the interactions between opportunistic fungi and their hosts, we investigated hydrogen peroxide (H2O2), nitric oxide and TNF-alpha production by peritoneal macrophages from Ehrlich tumour-bearing mice (TBM) during microbial infections. For this purpose, TBM at days 7, 14 and 21 of tumour progression were inoculated intraperitoneally with C. albicans and evaluated after 24 and 72 h. We observed that TBM showed significant increases in H2O2, TNF-alpha levels and fungal clearance at day 7 after C. albicans infection. However, as the tumour advanced, there was a progressive decline in the release of H2O2 and TNF-alpha that was paired with the dissemination of C. albicans. These results demonstrate that protective macrophage activities against Candida albicans are limited to the initial stages of tumour growth; continued solid tumour growth weakened the macrophage response and as a consequence, weakened the host's susceptibility to opportunistic infections
Asunto(s)
Animales , Ratones , Infecciones Oportunistas/complicaciones , Infecciones Oportunistas/inmunología , Candida albicans , Candidiasis/complicaciones , Candidiasis/inmunología , Carcinoma de Ehrlich/complicaciones , Carcinoma de Ehrlich/inmunología , Linfotoxina-alfa/biosíntesis , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/metabolismo , Peróxido de Hidrógeno/metabolismo , Óxido Nítrico/biosíntesisRESUMEN
This study used Ehrlich solid tumor as an experimental model for breast cancer to investigate the effects of thyroid hormones and castration on tumor development in adult female mice. Artificial hyperthyroidism was induced in animals, and after a 30-day-treatment, they received subcutaneous injection of neoplastic cells between left plantar cushions. We measured the growth of tumor inoculated in the paws for 10 days at necropsy. Hyperthyroidism induction led to significantly increased tumor size in non-castrated animals, and alterations were less intense in association with artificial hyperthyroidism and castration (p<0.05). Histomorphologic and histomorphometric analyses and neoplastic cell characterization were carried out by measuring nuclear diameter, by evaluating AgNORs, by mitotic count, and by measuring cell proliferation using immunohistochemical marker CDC47. At the end of the experiment, we noted metabolism and a decrease in cell proliferation in groups having received l-thyroxine, which were more evident in the non-castrated group (p<0.001).
Asunto(s)
Neoplasias de la Mama/patología , Carcinoma de Ehrlich/patología , Hipertiroidismo/patología , Ovariectomía , Animales , Antígenos Nucleares/análisis , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/metabolismo , Carcinoma de Ehrlich/complicaciones , Carcinoma de Ehrlich/metabolismo , Núcleo Celular/química , Núcleo Celular/patología , Proliferación Celular , Modelos Animales de Enfermedad , Femenino , Hipertiroidismo/inducido químicamente , Hipertiroidismo/complicaciones , Hipertiroidismo/metabolismo , Ratones , Índice Mitótico , Proteínas Nucleares/análisis , Proteínas Nucleares/metabolismo , Tiroxina/farmacologíaRESUMEN
The aim of the present study was to examine the protective effect of cystathionine as a cysteine precursor on doxorubicin toxicity in the liver of Ehrlich ascites tumor (EAT)-bearing mice and in the EAT cells. Both compounds were injected intraperitoneally alone or in combination at the following doses: cystathionine at 10 mg and doxorubicin at 5 mg per kg of body weight. In the liver of EAT-bearing mice, glutathione (GSH), cysteine and sulfane sulfur levels as well as the activities of: glutathione S-transferase, gamma-glutamyl transpeptidase, rhodanese and gamma-cystathionase significantly dropped in comparison with healthy animals. Administration of cystathionine elevated GSH and cysteine levels in the livers of EAT-bearing mice and reduced lipid peroxidation. Furthermore, cystathionine increased gamma-glutamyl transpeptidase activity, thereby activating gamma-glutamyl cycle, responsible for proper glutathione metabolism in the cells. Cystationine did not influence sulfane sulfur level and rhodanese and gamma-cystathionase activity in the livers of EAT-bearing mice. It was next shown that cystathionine administered in combination with doxorubicin protected against the drug toxicity since it elevated thiol level, lowering reactive oxygen species content and suppressing lipid peroxidation. This means that, cystathionine in the liver of EAT-bearing mice can both correct harmful effects of carcinogenesis, and protect the liver from doxorubicin cytotoxicity. In contrast, in EAT cells, cystathionine lowered GSH and cysteine levels and did not alter reactive oxygen species level, lipid peroxidation, and gamma-glutamyl transpeptidase activity. All these data indicate that cystathionine action is selectively beneficial for normal cells because it corrects harmful effects induced by EAT development and protects the organism against doxorubicin cytotoxicity without impairing cytotoxicity of this drug to tumor cells.
Asunto(s)
Antibióticos Antineoplásicos/antagonistas & inhibidores , Antibióticos Antineoplásicos/toxicidad , Carcinoma de Ehrlich/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Cistationina/farmacología , Doxorrubicina/antagonistas & inhibidores , Doxorrubicina/toxicidad , Fosfatasa Alcalina/metabolismo , Animales , Carcinoma de Ehrlich/complicaciones , Enfermedad Hepática Inducida por Sustancias y Drogas/complicaciones , Cistationina gamma-Liasa/metabolismo , Glutatión/metabolismo , Glutatión Transferasa/metabolismo , Indicadores y Reactivos , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Malondialdehído/metabolismo , Ratones , Especies Reactivas de Oxígeno/metabolismo , gamma-Glutamiltransferasa/metabolismoRESUMEN
This study addresses the interaction between Ehrlich ascites tumor and skeletal abdominal muscle, presenting quantitative analysis of ascites-induced angiogenesis and inflammation in this tissue of mice bearing-tumor. Time-dependent changes in the muscle (cellular activity, angiogenesis, inflammation and cytokines production) were assessed by morphometric, functional, and biochemical parameters at days 1, 4 and 8 after i.p. inoculation of Ehrlich tumor cells (2.5 x 10(7)). The number of cells stained with AgNOR technique (argyrophilic nucleolar organizer region) in the muscle, together with MTS assay used as markers of cellular activity increased progressively in parallel with the out flow rate of sodium fluorescein (blood flow index), hemoglobin content (vascular index) and VEGF production. Likewise, the inflammatory process in the muscle, as assessed by myeloperoxidase (MPO) and n-acethylglucosaminidase (NAG) activities and the levels of the chemokines, keratinocyte-derived chemokine (CXC1-3/KC) and macrophage-chemoattractant protein (CCL2/MCP-1) increased with tumor development. The combination of techniques used to describe angiogenesis and inflammation in a muscle model system has proved to be suited for quantitative measurements of microvascular changes and cellular infiltration occurring in the abdominal muscle wall of ascites-bearing mice. This study holds potential for investigating events and mechanisms associated with skeletal muscle response to neoplasic stimulus.
Asunto(s)
Carcinoma de Ehrlich/complicaciones , Músculo Esquelético/irrigación sanguínea , Miositis/etiología , Neovascularización Patológica/etiología , Animales , Citocinas/análisis , Citocinas/metabolismo , Hemoglobinas/análisis , Masculino , Ratones , Ratones Endogámicos BALB C , Músculo Esquelético/química , Músculo Esquelético/patología , Miositis/patología , Neovascularización Patológica/patologíaRESUMEN
BACKGROUND: The true therapeutic benefit of the use of natural products, especially acceptable dietary components such as curcumin, which can spare the normal cells and boost host immunity, has opened new horizons in cancer prevention and treatment. METHODS: In our model system we used Ehrlich's ascites carcinoma cells grown in peritoneal carity of Swiss albino mice and curcumin was fed every alternative day. RESULTS: Here, we report that curcumin administration to tumor-bearing mice decreased tumor cell number significantly in a dose-dependent manner. Furthermore, tumor-induced depletion of immune cell number of the host, as was evidenced from the decrease in bone marrow progenitor as well as thymic and splenic mononuclear cell numbers, was reintrated by curcumin. In fact, curcumin inhibited tumor-induced apoptosis of both thymocytes and splenocytes thereby restoring immune cell numbers to normal level in treated Ehrlich's ascites carcinoma-bearing mice. Moreover, curcumin was not toxic to the host; rather in tumor-bearing mice it inhibited hematopoietic toxicity, acted as a hepatoprotective agent and activated depressed anti-oxidant and detoxification systems. CONCLUSION: The ability of curcumin to regress tumor as well as to protect the host from tumor-induced immunosuppression and toxicity strongly supports the candidacy of curcumin as a potential agent for the dietary therapy of cancer.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Carcinoma de Ehrlich/tratamiento farmacológico , Curcumina/farmacología , Inmunidad Celular/efectos de los fármacos , Animales , Apoptosis , Carcinoma de Ehrlich/complicaciones , Carcinoma de Ehrlich/inmunología , Terapia de Inmunosupresión , Ratones , Monocitos , Bazo/citología , Timo/citologíaRESUMEN
We show that granulocytes (PMN) have a dual role in the development of Ehrlich Ascites Tumor (EAT) in mice. EAT intraperitoneal inoculation causes a local inflammatory reaction, ascites development and mortality that distinguish resistant and susceptible strains. In resistant mice (CAF1), there is a less pronounced PMN influx after EAT inoculation than in susceptible Swiss mice. Accordingly, the increase in peritoneal PMN numbers enhanced tumor growth in CAF1 mice, but had no effect in the susceptible Swiss animals. Contrastingly, PMN depletion had no effect in resistant mice but facilitated tumor growth in susceptible animals. Though no differences were noted between the strains in peritoneal cell spreading and hydrogen peroxide release after tumor inoculation, in vitro PMN cytotoxic activity against EAT was significantly higher in susceptible Swiss mice. These data indicate a paradoxical dual role for PMN against EAT: while they help control tumor development in susceptible animals, they seem to enhance tumor growth in resistant mice.
Asunto(s)
Carcinoma de Ehrlich/inmunología , Citotoxicidad Inmunológica , Inflamación/inmunología , Neutrófilos/inmunología , Análisis de Varianza , Animales , Anticuerpos Monoclonales/inmunología , Peso Corporal , Carcinoma de Ehrlich/complicaciones , Glucógeno/inmunología , Glucógeno/metabolismo , Peróxido de Hidrógeno/metabolismo , Inflamación/etiología , Inyecciones Intraperitoneales , Masculino , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Sales de Tetrazolio , Tiazoles , Factores de TiempoRESUMEN
The efficacy and safety of intraperitoneal administration of vincristine sulphate was determined in mice bearing Ehrlich ascitic carcinoma. The tumor bearing animals were administered with 0.5 mg/kg body weight (b.wt) of freshly prepared vincristine sulphate intraperitoneally on day 6 after tumor transplantation followed by drug administration once daily 5 days a week consecutively. The observations regarding the survival, alteration in the volume of peritoneal fluid, increase in life span and pathological changes in the liver, kidney, gastrointestinal tract and bone tissues were made. The vincristine sulphate treatment reduced the malignant cell population significantly and there were no significant changes in the histological picture of liver, kidney, bone, except the intestine, where atropy of villi demonstrating nests and cords of uniform small round cells were observed. Our experimental data suggests that intraperitoneal administration of vincristine is beneficial in malignant peritoneal effusion.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Líquido Ascítico/tratamiento farmacológico , Líquido Ascítico/etiología , Carcinoma de Ehrlich/complicaciones , Vincristina/uso terapéutico , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Líquido Ascítico/patología , Carcinoma de Ehrlich/patología , Supervivencia Celular/efectos de los fármacos , Sistema Digestivo/patología , Femenino , Tránsito Gastrointestinal/efectos de los fármacos , Inyecciones Intraperitoneales , Riñón/patología , Hígado/patología , Ratones , Ratas , Ratas Wistar , Análisis de Supervivencia , Vincristina/administración & dosificaciónRESUMEN
To assess the diagnostic and prognostic value of interleukin-6, interleukin 1 beta, and tumor necrosis factor-alpha assays in plasma and ascites, we measured these cytokines in eight patients with malignancy-related ascites and 32 patients with decompensated cirrhosis. Five patients had an episode of bacterial peritonitis, during which one or more ascitic fluid samples were analyzed. Interleukin-6 and tumor necrosis factor-alpha were not significantly different between the cirrhotic and the malignant groups: ascitic interleukin-6 13,816 +/- 15,314 vs 28,138 +/- 23,403 pg/ml, plasma interleukin-6 542 +/- 719 vs 559 +/- 604 pg/ml; ascitic tumor necrosis factor-alpha 19 +/- 50 vs 12 +/- 31 pg/ml, plasma tumor necrosis factor-alpha 3.4 +/- 8.2 vs 6.1 +/- 13.8 pg/ml. During an episode of bacterial peritonitis there was a significant increase only in ascitic interleukin-6 (133,268 +/- 99,743 pg/ml), which declined after antibiotic treatment. None of the parameters was associated with 6-month survival (11 of the 40 patients died within 6 months). There was a correlation (r = 0.675; p = 0.002) between plasma interleukin-6 levels and the Child-Pugh score in patients with cirrhosis, but not with the etiology of the liver disorder. Plasma interleukin-6 levels correlated with IgA levels (r = 0.649; p = 0.004) but not with C reactive protein, sedimentation rate, fibrinogen, IgM or IgG. These results do suggest that interleukin-6 is produced within the peritoneal cavity in hepatic and malignant ascites. There is a sharp increase in the local production of interleukin-6 during an episode of bacterial peritonitis.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Ascitis/etiología , Líquido Ascítico/química , Carcinoma de Ehrlich/complicaciones , Interleucina-6/análisis , Cirrosis Hepática/complicaciones , Adulto , Anciano , Animales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Factor de Necrosis Tumoral alfa/análisisRESUMEN
In the present study we investigated the inflammatory response induced by the inoculation of Ehrlich tumor cells (EAT) into the peritoneal cavity of mice. It was found that after inoculation of 10(3) EAT cells, the number of peritoneal leukocytes remained unchanged till the sixth day. Subsequently, the number of cells increased as a consequence of tumor growth. EAT cells did not induce influx of PMN leukocytes till six days after tumor implantation, but a significant influx was observed on the tenth day. Inoculation of the tumor cells did not induce production of H2O2 by peritoneal cells at any time examined and induced low levels of macrophage spreading only until the third day after tumor implantation but not later on. The levels of thromboxane in the peritoneal cavity were not affected by the presence of the tumor, whereas prostaglandin E2 levels were significantly increased at all times examined. The biological significance of these results on the evolution and escape of the tumor from host defense mechanisms is under investigation.
Asunto(s)
Carcinoma de Ehrlich/complicaciones , Inflamación/etiología , Cavidad Peritoneal/citología , Animales , Adhesión Celular , Recuento de Células , Dinoprostona/metabolismo , Peróxido de Hidrógeno/metabolismo , Inflamación/inmunología , Macrófagos/citología , Masculino , Ratones , Trasplante de Neoplasias , Tromboxano B2/metabolismoRESUMEN
Effect of tumor growth on the survival of circulating erythrocytes was studied in mice bearing a wide spectrum of experimental tumors. RBC half-life (t1/2), measured by 51Cr-labeling technique, decreased significantly (p less than 0.05) in all the tumor types studied, particularly in transplantable Sarcoma-180 and benzo(a)pyrene-induced primary fibrosarcoma. Changes in erythrocyte morphology like anisopoikilocytosis were also observed in the tumor hosts. Cross-transfusion of 51Cr-labeled RBCs between normal and tumor-bearing animals revealed that both intrinsic and extrinsic factors are responsible for shortened RBC survival. As far as the cellular abnormalities are concerned, the decrease in RBC t1/2 was not attributable to increased osmotic fragility as the cells were observed to be osmotically more resistant. Similarly, membrane sialic acid content was markedly elevated in the tumor hosts, thus the shortened erythrocyte life-span cannot be attributed to decrease in sialic acid content of the erythrocyte membrane.