Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
1.
Mol Cancer Ther ; 10(12): 2350-62, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21992792

RESUMO

Tumor cell proliferation requires both growth signals and sufficient cellular bioenergetics. The AMP-activated protein kinase (AMPK) pathway seems dominant over the oncogenic signaling pathway suppressing cell proliferation. This study investigated the preclinical efficacy of targeting the tumor bioenergetic pathway using a glycolysis inhibitor 2-deoxyglucose (2DG) and AMPK agonists, AICAR and metformin. We evaluated the in vitro antitumor activity of 2DG, metformin or AICAR alone, and 2DG in combination either with metformin or AICAR. We examined in vivo efficacy using xenograft mouse models. 2DG alone was not sufficient to promote tumor cell death, reflecting the limited efficacy showed in clinical trials. A combined use of 2DG and AICAR also failed to induce cell death. However, 2DG and metformin led to significant cell death associated with decrease in cellular ATP, prolonged activation of AMPK, and sustained autophagy. Gene expression analysis and functional assays revealed that the selective AMPK agonist AICAR augments mitochondrial energy transduction (OXPHOS) whereas metformin compromises OXPHOS. Importantly, forced energy restoration with methyl pyruvate reversed the cell death induced by 2DG and metformin, suggesting a critical role of energetic deprivation in the underlying mechanism of cell death. The combination of 2DG and metformin inhibited tumor growth in mouse xenograft models. Deprivation of tumor bioenergetics by dual inhibition of energy pathways might be an effective novel therapeutic approach for a broad spectrum of human tumors.


Assuntos
Desoxiglucose/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Metformina/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Desoxiglucose/administração & dosagem , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Metformina/administração & dosagem , Camundongos , Camundongos Nus , Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Cancer Prev Res (Phila) ; 4(8): 1306-15, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21505178

RESUMO

Lung cancer is the leading cause of cancer-related mortality worldwide. Early detection or prevention strategies are urgently needed to increase survival. Hyperplasia is the first morphologic change that occurs in the bronchial epithelium during lung cancer development, followed by squamous metaplasia, dysplasia, carcinoma in situ, and invasive tumor. This study was designed to determine the molecular mechanisms that control bronchial epithelium hyperplasia. Using primary normal human tracheobronchial epithelial (NHTBE) cells cultured by using the 3-dimensional (3D) organotypic method, we found that the epidermal growth factor receptor (EGFR) ligands, EGF, TGF-α, and amphiregulin induced hyperplasia, as determined by cell proliferation and multilayered epithelium formation. We also found that EGF induced increased cyclin D1 expression, which plays a critical role in bronchial hyperplasia; this overexpression was mediated by activating the mitogen-activated protein kinase pathway but not the phosphoinositide 3-kinase/Akt signaling pathway. Erlotinib, an EGFR tyrosine kinase inhibitor, and U0126, a MAP/ERK kinase (MEK) inhibitor, completely inhibited EGF-induced hyperplasia. Furthermore, a promoter analysis revealed that the activator protein-1 transcription factor regulates EGF-induced cyclin D1 overexpression. Activator protein-1 depletion by using siRNA targeting its c-Jun component completely abrogated EGF-induced cyclin D1 expression. In conclusion, we showed that bronchial hyperplasia can be modeled in vitro by using primary NHTBE cells maintained in a 3D organotypic culture. EGFR and MEK inhibitors completely blocked EGF-induced bronchial hyperplasia, suggesting that they have a chemopreventive role.


Assuntos
Brônquios/efeitos dos fármacos , Brônquios/patologia , Receptores ErbB/antagonistas & inibidores , Hiperplasia/patologia , Butadienos/farmacologia , Linhagem Celular Tumoral , Ciclina D1/metabolismo , Inibidores Enzimáticos/farmacologia , Cloridrato de Erlotinib , Humanos , Luciferases/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , MAP Quinase Quinase Quinases/antagonistas & inibidores , Modelos Biológicos , Nitrilas/farmacologia , Técnicas de Cultura de Órgãos/métodos , Quinazolinas/farmacologia , RNA Interferente Pequeno/metabolismo
3.
Cancer Prev Res (Phila) ; 4(2): 218-29, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21292635

RESUMO

Patients with oral premalignant lesion (OPL) have a high risk of developing oral cancer. Although certain risk factors, such as smoking status and histology, are known, our ability to predict oral cancer risk remains poor. The study objective was to determine the value of gene expression profiling in predicting oral cancer development. Gene expression profile was measured in 86 of 162 OPL patients who were enrolled in a clinical chemoprevention trial that used the incidence of oral cancer development as a prespecified endpoint. The median follow-up time was 6.08 years and 35 of the 86 patients developed oral cancer over the course. Gene expression profiles were associated with oral cancer-free survival and used to develop multivariate predictive models for oral cancer prediction. We developed a 29-transcript predictive model which showed marked improvement in terms of prediction accuracy (with 8% predicting error rate) over the models using previously known clinicopathologic risk factors. On the basis of the gene expression profile data, we also identified 2,182 transcripts significantly associated with oral cancer risk-associated genes (P value < 0.01; univariate Cox proportional hazards model). Functional pathway analysis revealed proteasome machinery, MYC, and ribosomal components as the top gene sets associated with oral cancer risk. In multiple independent data sets, the expression profiles of the genes can differentiate head and neck cancer from normal mucosa. Our results show that gene expression profiles may improve the prediction of oral cancer risk in OPL patients and the significant genes identified may serve as potential targets for oral cancer chemoprevention.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Perfilação da Expressão Gênica , Neoplasias Bucais/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/tratamento farmacológico , Feminino , Humanos , Isotretinoína/farmacologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/tratamento farmacológico , Análise de Sequência com Séries de Oligonucleotídeos , RNA Neoplásico/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Teratogênicos/farmacologia , Resultado do Tratamento , Adulto Jovem
4.
Hum Mol Genet ; 20(4): 820-6, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21106707

RESUMO

Mutagen sensitivity, a measurement of chromatid breaks induced by various mutagens in short-term cultures of peripheral blood lymphocytes, is an established risk factor for a number of cancers and is highly heritable. The purpose of this study is to identify genetic predictors of mutagen sensitivity. Therefore, we conducted a multi-stage genome-wide association study. The primary scan analyzed 539,437 autosomal SNPs in 673 healthy individuals, followed by validations in two independent sets of 575 and 259 healthy individuals, respectively. One SNP, rs8093763, on chromosome 18q21 showed significant association with bleomycin (BLM) sensitivity (combined P = 2.64 × 10⁻8). We observed significantly lower BLM-induced chromotid breaks for genotypes containing wild-type allele compared with the homozygous variant genotype in the discovery set (0.71 versus 0.90, P= 3.77 × 10⁻5) and in replication phase 1 (0.61 versus 0.84, P= 7.00 × 10⁻5). The result of replication phase 2 was not statistically significant (0.65 versus 0.68, P= 0.44). This SNP is approximately 64 kb from PMAIP1/Noxa, which is a radiation-inducible gene and exhibits higher expression in BLM-sensitive lymphoblastoid cell lines than insensitive cell lines upon BLM treatment. In conclusion, we identified a biologically plausible genetic variant on 18q21 near the PMAIP1/Noxa gene that is associated with BLM sensitivity.


Assuntos
Bleomicina/metabolismo , Bleomicina/toxicidade , Cromatina/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Estudos de Casos e Controles , Aberrações Cromossômicas/efeitos dos fármacos , Cromossomos Humanos Par 18 , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Mutagênicos/metabolismo , Mutagênicos/toxicidade , Polimorfismo de Nucleotídeo Único , População Branca , Adulto Jovem
5.
J Clin Oncol ; 27(12): 1976-82, 2009 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-19289628

RESUMO

PURPOSE: For patients with stage II to IV laryngeal cancer, radiation therapy (RT) either alone or with concurrent chemotherapy provides the highest rate of organ preservation but can be associated with functional impairment. Thus, we studied the use of induction chemotherapy with or without conservation laryngeal surgery (CLS). Our objectives were to study the sensitivity of laryngeal cancer to platinum-based chemotherapy alone and to highlight the efficacy of CLS in this setting. PATIENTS AND METHODS: Thirty-one previously untreated patients with laryngeal cancer (T2-4, N0-1, M0), who were resectable with CLS, were enrolled. Patients received three to four cycles of paclitaxel, ifosfamide, and cisplatin (TIP) chemotherapy, and response was assessed histologically. Patients with partial response (PR) proceeded to CLS. Patients achieving pathologic complete response (pCR) received an additional three cycles of TIP and no other treatment. RESULTS: Thirty patients were assessable for response. With TIP chemotherapy alone, 11 patients (37%) achieved pCR, 10 of whom (33%) remain alive with durable disease remission and no evidence of recurrence over a median follow-up time of 5 years. Nineteen patients (63%) treated with TIP alone achieved PR. The overall laryngeal preservation (LP) rate was 83%, and only five patients (16%) required postoperative RT. No patient required a gastrostomy tube or tracheotomy. CONCLUSION: Chemotherapy alone in selected patients with T2-4, N0-1 laryngeal cancer can provide durable disease remission at 5 years. For patients with PR, CLS provides a high rate of LP. This prospective study suggests that chemotherapy alone may cure selected patients with laryngeal cancer, warranting further prospective investigation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Laríngeas/tratamento farmacológico , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Terapia Combinada , Feminino , Seguimentos , Humanos , Ifosfamida/administração & dosagem , Neoplasias Laríngeas/patologia , Laringectomia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Prognóstico , Estudos Prospectivos , Indução de Remissão , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
6.
Clin Cancer Res ; 9(15): 5532-9, 2003 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-14654533

RESUMO

PURPOSE: This study was conducted to develop biologically relevant animal models of human lung cancer that are reproducible, inexpensive, and easy to perform. EXPERIMENTAL DESIGN: Human lung adenocarcinoma (PC14PE6), bronchioloalveolar carcinoma (NCI-H358), squamous cell carcinoma (NCI-H226), poorly differentiated non-small cell lung cancer (NCI-H1299 and A549), or small cell lung cancer (NCI-H69) cells in Matrigel were injected percutaneously into the left lungs of nude mice. The growth pattern of the different lung cancer tumors was studied. For PC14PE6 and NCI-H358, the growth pattern in the subcutis and the response to paclitaxel were also studied. RESULTS: As is observed for human primary lung cancer, tumors formed from a single focus of disease and progressed to a widespread and fatal thoracic process characterized by diffuse dissemination of lung cancer in both lungs and metastasis to intra- and extrathoracic lymph nodes. When the lung cancer cell lines were implanted s.c., systemic therapy with paclitaxel induced tumor regression. However, only a limited therapeutic response to paclitaxel was observed when the same cells were implanted orthotopically into the lung. Immunohistochemical analysis of tumor tissue revealed increased expression of the proangiogenic factors interleukin 8, basic fibroblast growth factor, and vascular endothelial growth factor/vascular permeability factor. CONCLUSIONS: Our orthotopic models of human lung cancer confirm the "seed and soil" concept and likely provide more clinically relevant systems for the study of both non-small cell lung cancer and small cell lung cancer biology, and for characterizing novel therapeutic strategies.


Assuntos
Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Paclitaxel/uso terapêutico , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/fisiopatologia , Linhagem Celular Tumoral , Fator 2 de Crescimento de Fibroblastos/análise , Humanos , Interleucina-8/análise , Neoplasias Pulmonares/fisiopatologia , Metástase Linfática , Camundongos , Camundongos Nus , Modelos Biológicos , Metástase Neoplásica , Neovascularização Patológica/patologia , Fator A de Crescimento do Endotélio Vascular/análise
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...