Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Front Oncol ; 8: 23, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29484285

RESUMO

Despite substantial effort and resources dedicated to drug discovery and development, new anticancer agents often fail in clinical trials. Among many reasons, the lack of reliable predictive preclinical cancer models is a fundamental one. For decades, immortalized cancer cell cultures have been used to lay the groundwork for cancer biology and the quest for therapeutic responses. However, cell lines do not usually recapitulate cancer heterogeneity or reveal therapeutic resistance cues. With the rapidly evolving exploration of cancer "omics," the scientific community is increasingly investigating whether the employment of short-term patient-derived tumor cell cultures (two- and three-dimensional) and/or patient-derived xenograft models might provide a more representative delineation of the cancer core and its therapeutic response. Patient-derived cancer models allow the integration of genomic with drug sensitivity data on a personalized basis and currently represent the ultimate approach for preclinical drug development and biomarker discovery. The proper use of these patient-derived cancer models might soon influence clinical outcomes and allow the implementation of tailored personalized therapy. When assessing drug efficacy for the treatment of glioblastoma multiforme (GBM), currently, the most reliable models are generated through direct injection of patient-derived cells or more frequently the isolation of glioblastoma cells endowed with stem-like features and orthotopically injecting these cells into the cerebrum of immunodeficient mice. Herein, we present the key strengths, weaknesses, and potential applications of cell- and animal-based models of GBM, highlighting our experience with the glioblastoma stem-like patient cell-derived xenograft model and its utility in drug discovery.

2.
Cell Stem Cell ; 21(1): 35-50.e9, 2017 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-28602620

RESUMO

Functionally relevant markers of glioblastoma stem-like cells (GSCs) have potential for therapeutic targeting to treat this aggressive disease. Here we used generation and screening of thousands of monoclonal antibodies to search for receptors and signaling pathways preferentially enriched in GSCs. We identified integrin α7 (ITGA7) as a major laminin receptor in GSCs and in primary high-grade glioma specimens. Analyses of mRNA profiles in comprehensive datasets revealed that high ITGA7 expression negatively correlated with survival of patients with both low- and high-grade glioma. In vitro and in vivo analyses showed that ITGA7 plays a key functional role in growth and invasiveness of GSCs. We also found that targeting of ITGA7 by RNAi or blocking mAbs impaired laminin-induced signaling, and it led to a significant delay in tumor engraftment plus a strong reduction in tumor size and invasion. Our data, therefore, highlight ITGA7 as a glioblastoma biomarker and candidate therapeutic target.


Assuntos
Anticorpos Monoclonais Murinos/farmacologia , Anticorpos Antineoplásicos/farmacologia , Biomarcadores Tumorais/antagonistas & inibidores , Glioblastoma/tratamento farmacológico , Cadeias alfa de Integrinas/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Animais , Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Sistemas de Liberação de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Glioblastoma/metabolismo , Glioblastoma/patologia , Células HeLa , Humanos , Cadeias alfa de Integrinas/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas de Neoplasias/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Target Oncol ; 12(4): 449-462, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28589491

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) represents one of the most lethal cancers worldwide due to therapy resistance and disease recurrence. Tumor relapse following treatment could be driven by the persistence of liver cancer stem-like cells (CSCs). The protein BMI1 is a member of the polycomb epigenetic factors governing cellular self-renewal, proliferation, and stemness maintenance. BMI1 expression also correlates with poor patient survival in various cancer types. OBJECTIVE: We aimed to elucidate the extent to which BMI1 can be used as a potential therapeutic target for CSC eradication in HCC. METHODS: We have recently participated in characterizing the first known pharmacological small molecule inhibitor of BMI1. Here, we synthesized a panel of novel BMI1 inhibitors and examined their ability to alter cellular growth and eliminate cancer progenitor/stem-like cells in HCC with different p53 backgrounds. RESULTS: Among various molecules examined, RU-A1 particularly downregulated BMI1 expression, impaired cell viability, reduced cell migration, and sensitized HCC cells to 5-fluorouracil (5-FU) in vitro. Notably, long-term analysis of HCC survival showed that, unlike chemotherapy, RU-A1 effectively reduced CSC content, even as monotherapy. BMI1 inhibition with RU-A1 diminished the number of stem-like cells in vitro more efficiently than the model compound C-209, as demonstrated by clonogenic assays and impairment of CSC marker expression. Furthermore, xenograft assays in zebrafish showed that RU-A1 abrogated tumor growth in vivo. CONCLUSIONS: This study demonstrates the ability to identify agents with the propensity for targeting CSCs in HCC that could be explored as novel treatments in the clinical setting.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Complexo Repressor Polycomb 1/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antineoplásicos/química , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Células HEK293 , Células Hep G2 , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Complexo Repressor Polycomb 1/biossíntese , Complexo Repressor Polycomb 1/genética , Bibliotecas de Moléculas Pequenas/química , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
4.
Clin Cancer Res ; 22(24): 6176-6191, 2016 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-27307599

RESUMO

PURPOSE: Current prostate cancer management calls for identifying novel and more effective therapies. Self-renewing tumor-initiating cells (TICs) hold intrinsic therapy resistance and account for tumor relapse and progression. As BMI-1 regulates stem cell self-renewal, impairing BMI-1 function for TIC-tailored therapies appears to be a promising approach. EXPERIMENTAL DESIGN: We have previously developed a combined immunophenotypic and time-of-adherence assay to identify CD49bhiCD29hiCD44hi cells as human prostate TICs. We utilized this assay with patient-derived prostate cancer cells and xenograft models to characterize the effects of pharmacologic inhibitors of BMI-1. RESULTS: We demonstrate that in cell lines and patient-derived TICs, BMI-1 expression is upregulated and associated with stem cell-like traits. From a screened library, we identified a number of post-transcriptional small molecules that target BMI-1 in prostate TICs. Pharmacologic inhibition of BMI-1 in patient-derived cells significantly decreased colony formation in vitro and attenuated tumor initiation in vivo, thereby functionally diminishing the frequency of TICs, particularly in cells resistant to proliferation- and androgen receptor-directed therapies, without toxic effects on normal tissues. CONCLUSIONS: Our data offer a paradigm for targeting TICs and support the development of BMI-1-targeting therapy for a more effective prostate cancer treatment. Clin Cancer Res; 22(24); 6176-91. ©2016 AACR.


Assuntos
Antineoplásicos/farmacologia , Autorrenovação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Complexo Repressor Polycomb 1/metabolismo , Neoplasias da Próstata/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
5.
Curr Pharm Des ; 20(24): 3973-81, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24138717

RESUMO

The advent of molecular targeted agents is changing the treatment of solid tumors. In non-small-cell lung cancer, compounds directed against oncogenic proteins offer novel therapeutic opportunities for a fraction of patients whose tumors harbor specific genetic defects. With the increased level of resolution achieved by high-throughput technologies, the taxonomy of lung cancer is rapidly changing. For instance, by cataloguing genetic abnormalities in squamous cell lung cancer the Cancer Genome Atlas Network revealed the existence of multiple molecular entities, each one characterized by specific molecular abnormalities, and by a different spectrum of activated/ inactivated molecular networks. Although this increased complexity could be perceived as a further drawback in effective anticancer therapy, on the other hand the combined interrogation of genomic and proteomic data is expected to provide the whole molecular map of each tumor, and to determine the information flow in the explored biological system. In particular, novel genetic and proteomic approaches are offering the opportunity for matching specific genetic defects and aberrant protein-protein interactions with active pathway-targeted inhibitors. Moreover, the isolation and characterization of a cellular pool endowed with stem-like traits, and able to recapitulate the parental disease in animals, is enabling investigators to recreate the individual patient tumor in the laboratory. In this article, we discuss how novel technologies and cellular and animal models, applied to lung cancer research, hold the potential to foster a new wave of biomarker-driven clinical trials.


Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Terapia de Alvo Molecular , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Genótipo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia
6.
Stem Cells ; 30(9): 1819-30, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22753241

RESUMO

Tumor-initiating cells are responsible for tumor maintenance and relapse in solid and hematologic cancers. Although tumor-initiating cells were initially believed to be mainly quiescent, rapidly proliferating tumorigenic cells were found in breast cancer. In colon cancer, the proliferative activity of the tumorigenic population has not been defined, although it represents an essential parameter for the development of more effective therapeutic strategies. Here, we show that tumorigenic colon cancer cells can be found in a rapidly proliferating state in vitro and in vivo, both in human tumors and mouse xenografts. Inhibitors of polo-like kinase1 (Plk1), a mitotic kinase essential for cell proliferation, demonstrated maximal efficiency over other targeted compounds and chemotherapeutic agents in inducing death of colon cancer-initiating cells in vitro. In vivo, Plk1 inhibitors killed CD133(+) colon cancer cells leading to complete growth arrest of colon cancer stem cell-derived xenografts, whereas chemotherapeutic agents only slowed tumor progression. While chemotherapy treatment increased CD133(+) cell proliferation, treatment with Plk1 inhibitors eliminated all proliferating tumor-initiating cells. Quiescent CD133(+) cells that survived the treatment with Plk1 inhibitors could be killed by subsequent Plk1 inhibition when they exited from quiescence. Altogether, these results provide a new insight into the proliferative status of colon tumor-initiating cells both in basal conditions and in response to therapy and indicate Plk1 inhibitors as potentially useful in the treatment of colorectal cancer.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Neoplasias do Colo/enzimologia , Neoplasias do Colo/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Antígeno AC133 , Animais , Antígenos CD/biossíntese , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/fisiologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/deficiência , Proteínas de Ciclo Celular/genética , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Glicoproteínas/biossíntese , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos NOD , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Peptídeos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Pteridinas/farmacologia , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Transplante Heterólogo , Quinase 1 Polo-Like
7.
Anal Chim Acta ; 586(1-2): 326-9, 2007 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-17386731

RESUMO

Oxytetracycline (OXY) is a broad-range antimicrobial routinely used in pig production, at doses in the range of few g/kg of medicated feed, during the weaning period. It could persist at ppm level in pig liquid manure that routinely is used for organic fertilisation. In the present work we describe a methodology to study OXY environmental fate in arable land where crops are cultivated for animal feeding purposes. A liquid-liquid extraction followed by metal chelate affinity chromatography was applied to environmental samples of manures and soils drawn within a case-control study. Extracts were then analysed by high performance liquid chromatography with UV/DAD detection, using a reverse phase column, and expressing the results as 4-epioxytetracycline epimer. Results indicate OXY is well retained at mg kg(-1) levels in soil exposed to contaminated pig manure fertilisation. Such compartment could constitute an abiotic reservoir for the systemic and/or for the external contamination of corn.


Assuntos
Monitoramento Ambiental/métodos , Oxitetraciclina/análise , Poluentes do Solo/análise , Animais , Técnicas de Química Analítica/métodos , Cromatografia de Afinidade , Cromatografia Líquida de Alta Pressão/métodos , Fertilizantes , Concentração de Íons de Hidrogênio , Esterco , Reprodutibilidade dos Testes , Solo , Suínos , Tetraciclina/análise , Zea mays/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...