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1.
Clin Cancer Res ; 18(17): 4600-11, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22791882

RESUMO

PURPOSE: During cell-cycle progression, D-cyclins activate cyclin-dependent kinases (CDKs) 4/6 to inactivate Rb, permitting E2F1-mediated S-phase gene transcription. This critical pathway is typically deregulated in cancer, and novel inhibitory strategies would be effective in a variety of tumors. The protein synthesis inhibitor silvestrol has potent activity in B-cell leukemias via the mitochondrial pathway of apoptosis, and also reduces cyclin D1 expression in breast cancer and lymphoma cell lines. We hypothesized that this dual activity of silvestrol would make it especially effective in malignancies driven by aberrant cyclin D1 expression. EXPERIMENTAL DESIGN: Mantle cell lymphoma (MCL), characterized by elevated cyclin D1, was used as a model to test this approach. The cyclin D/Rb/E2F1 pathway was investigated in vitro using MCL cell lines and primary tumor cells. Silvestrol was also evaluated in vivo using an aggressive model of MCL. RESULTS: Silvestrol showed low nanomolar potency both in MCL cell lines and primary MCL tumor cells. D-cyclins were depleted with just 10 nmol/L silvestrol at 16 hours, with subsequent reductions of phosphorylated Rb, E2F1 protein, and E2F1 target transcription. As showed in other leukemias, silvestrol caused Mcl-1 depletion followed by mitochondrial depolarization and caspase-dependent apoptosis, effects not related to inhibition of CDK4/6. Silvestrol significantly (P < 0.0001) prolonged survival in a MCL xenograft model without detectable toxicity. CONCLUSIONS: These data indicate that silvestrol effectively targets the cyclin/CDK/Rb pathway, and additionally induces cytotoxicity via intrinsic apoptosis. This dual activity may be an effective therapeutic strategy in MCL and other malignancies.


Assuntos
Ciclina D1 , Fator de Transcrição E2F1 , Linfoma de Célula do Manto , Triterpenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Ciclina D1/genética , Ciclina D1/metabolismo , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F1/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Linfoma de Célula do Manto/terapia , Redes e Vias Metabólicas , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transplante Heterólogo
2.
Mol Vis ; 14: 806-14, 2008 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-18449354

RESUMO

PURPOSE: To characterize the crystallin content of the zebrafish lens using two-dimensional gel electrophoresis (2-DE). These data will facilitate future investigations of vertebrate lens development, function, and disease. METHODS: Adult zebrafish lens proteins were separated by 2-DE, and the resulting spots were identified by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). The relative proportion of each crystallin was quantified by image analysis, and phosphospecific staining was used to identify phosphorylated alpha-crystallins. The proportion of each crystallin in the soluble and insoluble fraction of the lens was also determined by resolving these lens fractions separately by 2-DE. RESULTS: alpha-, beta-, and gamma-crystallins comprised 7.8, 36.0, and 47.2% of the zebrafish lens, respectively. While the alpha-crystallin content of the zebrafish lens is less than the amounts found in the human lens, the ratio of alphaA:alphaB crystallin is very similar. The phosphorylation pattern of zebrafish alphaA-crystallins was also similar to that of humans. The most abundant gamma-crystallins were the diverse gammaMs, comprising 30.5% of the lens. Intact zebrafish crystallins were generally more common in the soluble fraction with truncated versions more common in the insoluble fraction. CONCLUSIONS: While the total alpha- and gamma-crystallin content of the zebrafish lens differs from that of humans, similarities in alpha-crystallin ratios and modifications and a link between crystallin truncation and insolubility suggest that the zebrafish is a suitable model for the vertebrate lens. The proteome map provided here will be of value to future studies of lens development, function, and disease.


Assuntos
Cristalinas/metabolismo , Regulação da Expressão Gênica , Cristalino/química , Proteoma/análise , Peixe-Zebra/metabolismo , Animais , Densitometria , Eletroforese em Gel Bidimensional , Humanos , Proteínas Mutantes/metabolismo , Fosfoproteínas/metabolismo , Homologia de Sequência de Aminoácidos , Solubilidade , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , alfa-Cristalinas/química , alfa-Cristalinas/metabolismo , beta-Cristalinas/química , beta-Cristalinas/metabolismo , gama-Cristalinas/química , gama-Cristalinas/metabolismo
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