Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Curr Pharm Des ; 22(34): 5300-5310, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27339432

RESUMO

Lung cancer (LC) remains the leading cause of cancer mortality worldwide, and non-small cell LC (NSCLC) represents 80% of all LC. Oxidative stress and inflammation, autophagy, ubiquitin-proteasome system, nuclear factor (NF)-κB, and mitogen activated protein kinases (MAPK) participate in LC pathophysiology. Currently available treatment for LC is limited and in vivo models are lacking. We hypothesized that antioxidants and NF- κB, MAPK, and proteasome inhibitors may exert an antitumoral response through attenuation of several key biological mechanisms that promote tumorigenesis and cancer cell growth. Body and tumor weights, oxidative stress, antioxidants, inflammation, NF-κB p65 expression, fibulins, apoptosis, autophagy, tumor and stroma histology were evaluated in the subcutaneous tumor of LC (LP07 adenocarcinoma) BALB/c mice, with and without concomitant treatment with NF-κB (sulfasalazine), MEK (U0126), and proteasome (bortezomib) inhibitors, and N-acetyl cysteine (NAC). Compared to LC control mice, in subcutanous tumors, the four pharmacological agents reduced oxidative stress markers and tumor proliferation (ki-67). Inflammation and NF-κB p65 expression were attenuated by NF-κB and MAPK inhibitors, and the latter also enhanced apoptotic markers. Catalase was induced by the three inhibitors, while bortezomib also promoted superoxide dismutase expression. NF-κB and MEK inhibitors significantly reduced tumor burden through several biological mechanisms that favored tumor degradation and attenuated tumor proliferation. These two pharmacological agents may enhance the anti-tumor activity of selectively targeted therapeutic strategies for LC. Proteasomal inhibition using bortezomib rather promotes tumor degradation, while treatment with antioxidants cannot be recommended. This experimental model supports the use of adjuvant drugs for the improvement of LC treatment.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimioterapia Adjuvante , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Estresse Oxidativo/efeitos dos fármacos
2.
J Immunol ; 194(7): 3452-62, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25740944

RESUMO

Myeloid-derived suppressor cells (MDSCs) are key regulatory cells that control inflammation and promote tumor-immune escape. To date, no specific immunomodulatory drug has proven efficacy in targeting the expansion and/or function of these cells in different pathophysiologic settings. In this study, we identified a context-dependent effect of the nonsteroidal anti-inflammatory drug indomethacin (IND) on MDSCs, depending on whether they were derived from tumor microenvironments (TME) or from tumor-free microenvironments (TFME). Treatment of mice bearing the LP07 lung adenocarcinoma with IND inhibited the suppressive activity of splenic MDSCs, which restrained tumor growth through mechanisms involving CD8(+) T cells. The same effect was observed when MDSCs were treated with IND and conditioned media from LP07 tumor cells in vitro. However, in the absence of a tumor context, IND enhanced the intrinsic suppressive function of MDSCs and amplified their protumoral activity. In a model of autoimmune neuroinflammation, IND-treated MDSCs differentiated in TFME attenuated inflammation, whereas IND-treated MDSCs differentiated in TME aggravated clinical symptoms and delayed resolution of the disease. Mechanistically, IND reduced arginase activity as well as NO and reactive oxygen species production in MDSCs differentiated in TME but not in TFME. Moreover, expression of the C/EBP-ß transcription factor isoforms correlated with the suppressive activity of IND-treated MDSCs. Our study unveils the dual and context-dependent action of IND, a drug that serves both as an anti-inflammatory and anticancer agent, which differentially affects MDSC activity whether these cells are derived from TME or TFME. These results have broad clinical implication in cancer, chronic inflammation and autoimmunity.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Microambiente Celular/efeitos dos fármacos , Microambiente Celular/imunologia , Indometacina/farmacologia , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Animais , Autoimunidade/efeitos dos fármacos , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Imunofenotipagem , Camundongos , Modelos Biológicos , Células Mieloides/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Óxido Nítrico/metabolismo , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologia
3.
J Cell Physiol ; 229(11): 1660-72, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24615622

RESUMO

Cachexia is a relevant comorbid condition of chronic diseases including cancer. Inflammation, oxidative stress, autophagy, ubiquitin-proteasome system, nuclear factor (NF)-κB, and mitogen-activated protein kinases (MAPK) are involved in the pathophysiology of cancer cachexia. Currently available treatment is limited and data demonstrating effectiveness in in vivo models are lacking. Our objectives were to explore in respiratory and limb muscles of lung cancer (LC) cachectic mice whether proteasome, NF-κB, and MAPK inhibitors improve muscle mass and function loss through several molecular mechanisms. Body and muscle weights, limb muscle force, protein degradation and the ubiquitin-proteasome system, signaling pathways, oxidative stress and inflammation, autophagy, contractile and functional proteins, myostatin and myogenin, and muscle structure were evaluated in the diaphragm and gastrocnemius of LC (LP07 adenocarcinoma) bearing cachectic mice (BALB/c), with and without concomitant treatment with NF-κB (sulfasalazine), MAPK (U0126), and proteasome (bortezomib) inhibitors. Compared to control animals, in both respiratory and limb muscles of LC cachectic mice: muscle proteolysis, ubiquitinated proteins, autophagy, myostatin, protein oxidation, FoxO-1, NF-κB and MAPK signaling pathways, and muscle abnormalities were increased, while myosin, creatine kinase, myogenin, and slow- and fast-twitch muscle fiber size were decreased. Pharmacological inhibition of NF-κB and MAPK, but not the proteasome system, induced in cancer cachectic animals, a substantial restoration of muscle mass and force through a decrease in muscle protein oxidation and catabolism, myostatin, and autophagy, together with a greater content of myogenin, and contractile and functional proteins. Attenuation of MAPK and NF-κB signaling pathway effects on muscles is beneficial in cancer-induced cachexia.


Assuntos
Autofagia , Caquexia/tratamento farmacológico , Caquexia/etiologia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Debilidade Muscular/tratamento farmacológico , Músculo Esquelético/patologia , Proteólise , Animais , Autofagia/efeitos dos fármacos , Ácidos Borônicos/farmacologia , Ácidos Borônicos/uso terapêutico , Bortezomib , Butadienos/farmacologia , Butadienos/uso terapêutico , Linhagem Celular Tumoral , Inflamação/complicações , Inflamação/patologia , Inflamação/fisiopatologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/fisiopatologia , Camundongos , Camundongos Endogâmicos BALB C , Contração Muscular/efeitos dos fármacos , Proteínas Musculares/metabolismo , Debilidade Muscular/etiologia , Debilidade Muscular/patologia , Debilidade Muscular/fisiopatologia , Músculo Esquelético/anormalidades , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , NF-kappa B/metabolismo , Nitrilas/farmacologia , Nitrilas/uso terapêutico , Oxirredução , Proteólise/efeitos dos fármacos , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Sulfassalazina/farmacologia , Sulfassalazina/uso terapêutico , Tirosina/metabolismo , Aumento de Peso/efeitos dos fármacos
4.
Pancreas ; 42(7): 1060-9, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23695799

RESUMO

OBJECTIVE: This study aimed to investigate whether the overexpression of protein kinase C ß1 (PKCß1) is able to modulate the malignant phenotype displayed by the human ductal pancreatic carcinoma cell line PANC1. METHODS: PKCß1 overexpression was achieved using a stable transfection approach. PANC1-PKCß1 and control cells were analyzed both in vitro and in vivo. RESULTS: PANC1-PKCß1 cells displayed a lower growth capacity associated with the down-regulation of the MEK/ERK pathway and cyclin expression. Furthermore, PKCß1 overexpression was associated with an enhancement of cell adhesion to fibronectin and with reduced migratory and invasive phenotypes. In agreement with these results, PANC1-PKCß1 cells showed an impaired ability to secrete proteolytic enzymes. We also found that PKCß1 overexpressing cells were more resistant to cell death induced by serum deprivation, an event associated with G0/G1 arrest and the modulation of PI3K/Akt and NF-κB pathways. Most notably, the overexpression of PKCß1 completely abolished the ability of PANC1 cells to induce tumors in nude mice. CONCLUSIONS: Our results established an important role for PKCß1 in PANC1 cells suggesting it would act as a suppressor of tumorigenic behavior in pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático/enzimologia , Carcinoma Ductal Pancreático/etiologia , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/etiologia , Proteína Quinase C beta/metabolismo , Animais , Carcinoma Ductal Pancreático/patologia , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Xenoenxertos , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Transplante de Neoplasias , Neoplasias Pancreáticas/patologia , Peptídeo Hidrolases/metabolismo , Proteína Quinase C beta/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima
5.
Int J Cancer ; 110(6): 825-30, 2004 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-15170663

RESUMO

Mice bearing LP07 lung adenocarcinoma show some characteristics that are similar to those present in patients with NSCLC. LP07 tumor-bearing mice develop the paraneoplastic syndromes of cachexia, leukocytosis and hypercalcemia. These symptoms may be partly due to a systemic inflammatory response. Our aim was to determine if treatment with NSAIDs would lower tumor and metastasis growth and their accompanying syndromes. The nonselective COX inhibitor indomethacin and the selective COX-2 inhibitor celecoxib reduced tumor growth and metastasis outcome in s.c. LP07 tumor-bearing mice. Both drugs also inhibited the development of leukocytosis and the weight loss associated with LP07 progression. Serum levels of the inflammatory cytokines IL-1beta and IL-6, mediators of cachexia, were modulated by NSAIDs. Inhibition of in vitro migration and invasion and reduction in angiogenesis were attained when cells were treated with either indomethacin or celecoxib. MMP-9 activity was also reduced in conditioned media from LP07 cells treated with celecoxib. These data suggest that several processes implicated in tumor progression can be modulated with NSAID treatment. Improvement in performance status through modulation of cachexia may offer a possibility for combining anti-inflammatory treatments with more aggressive therapies.


Assuntos
Adenocarcinoma/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Síndromes Paraneoplásicas/prevenção & controle , Adenocarcinoma/patologia , Animais , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quimiotaxia/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/uso terapêutico , Citocinas/análise , Progressão da Doença , Feminino , Indometacina/uso terapêutico , Lactonas/uso terapêutico , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Invasividade Neoplásica/prevenção & controle , Sulfonas
6.
J Pain Symptom Manage ; 27(1): 85-95, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14711473

RESUMO

Systemic syndromes characterized by a persistent activity of circulating mediators (cytokines) are frequently present with advanced cancer. We grouped under the general heading of "Systemic Immune-Metabolic Syndrome (SIMS)" a particular variety of distressing systemic syndrome characterized by dysregulation of the psycho-neuro-immune-endocrine homeostasis, with overlapping clinical manifestations. SIMS may include cachexia, anorexia, nausea, early satiety, fatigue, tumor fever, cognitive changes and superinfection. The aim of this study was to ameliorate some of the SIMS symptoms in a homogeneous group of lung adenocarcinoma patients using a multitargeted therapy. Fifteen patients with evidence of SIMS were studied. SIMS was defined as the presence of weight loss, anorexia, fatigue performance status>/=2 and acute-phase protein response. Patients received medroxyprogesterone (MPA) (500 mg twice daily), celecoxib (200 mg twice daily), plus oral food supplementation for 6 weeks. After treatment, 13 patients either had stable weight (+/- 1%) or had gained weight. There were significant differences in improvement of body-weight-change rate, nausea, early satiety, fatigue, appetite and performance status. Patients who had any kind of lung infection showed higher levels of IL-10 compared to non-infected patients (P=0.039). Our results suggest that patients with advanced lung adenocarcinoma, treated with MPA, celecoxib and dietary intervention, might have considerable improvement in certain SIMS outcomes. This multitargeted symptomatic approach deserves further study.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antineoplásicos/uso terapêutico , Caquexia/terapia , Fadiga/terapia , Medroxiprogesterona/uso terapêutico , Sulfonamidas/uso terapêutico , Superinfecção/terapia , Adenocarcinoma/complicações , Adulto , Idoso , Caquexia/dietoterapia , Caquexia/etiologia , Celecoxib , Fadiga/dietoterapia , Fadiga/etiologia , Feminino , Humanos , Neoplasias Pulmonares/complicações , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Pirazóis , Superinfecção/dietoterapia , Superinfecção/etiologia , Síndrome
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...