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1.
Oncogene ; 29(48): 6314-22, 2010 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-20802532

RESUMO

The development of resistance against chemotherapy remains one of the major challenges in the clinical management of leukemia. There is still limited insight into the molecular mechanisms that maintain the chemotherapy-resistant phenotype, despite the obvious clinical relevance that such knowledge would have. In this study, we show that the chemotherapy-resistant phenotype of myeloid leukemia cells correlates with activation of the Hedgehog (Hh) pathway, whereas in chemosensitive cells, such activation is less pronounced. Importantly, the overexpression of Hh pathway components induces chemoprotection and inhibition of the pathway reverts chemoresistance of Lucena-1 cells, apparently by interfering with P-glycoprotein-dependent drug resistance. Our data thus identify the Hh pathway as an essential component of multidrug resistance (MDR) myeloid leukemia and suggest that targeting the Hh pathway might be an interesting therapeutic avenue for overcoming MDR resistance in myeloid leukemia.


Assuntos
Proteínas Hedgehog/fisiologia , Leucemia Mieloide/tratamento farmacológico , Transdução de Sinais/fisiologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/análise , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos
2.
J Thromb Haemost ; 7(2): 290-8, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19036066

RESUMO

BACKGROUND: Inhibition of specific coagulation pathways such as the factor VIIa-tissue factor complex has been shown to attenuate ischemia/reperfusion (I/R) injury, but the cellular mechanisms have not been explored. OBJECTIVES: To determine the cellular mechanisms involved in the working mechanism of active site inhibited factor VIIa (ASIS) in the protection against myocardial I/R injury. METHODS: We investigated the effects of a specific mouse recombinant in a mouse model of myocardial I/R injury. One hour of ischemia was followed by 2, 6 or 24 h of reperfusion. Mouse ASIS or placebo was administered before and after induction of reperfusion. RESULTS: ASIS administration reduced myocardial I/R injury by more than 40% at three reperfusion times. Multiplex ligation dependent probe amplification (MLPA) analysis showed reduced mRNA expression in the ischemic myocardium of CD14, TLR-4, interleukin-1 (IL-1) receptor-associated kinase (IRAK) and IkappaBalpha upon ASIS administration, indicative of inhibition of toll-like receptor-4 (TLR-4) and subsequent nuclear factor-kappaB (NF-kappaB) mediated cell signaling. Levels of nuclear activated NF-kappaB and proteins influenced by the NF-kappaB pathway including tissue factor (TF) and IL-6 that were increased after I/R, were attenuated upon ASIS administration. After 6 and 24 h of reperfusion, neutrophil infiltration into the area of infarction was decreased upon ASIS administration. There was, however, no evidence of an effect of ASIS on apoptosis (Tunel staining and MLPA analysis). CONCLUSIONS: We conclude that the diminished amount of myocardial I/R injury after ASIS administration is primarily due to attenuated inflammation-related lethal I/R injury, probably mediated through the NF-kappaB mechanism.


Assuntos
Fator VIIa/farmacologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , Fator VIIa/administração & dosagem , Inflamação , Camundongos , Isquemia Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , NF-kappa B/metabolismo , RNA Mensageiro/análise , RNA Mensageiro/efeitos dos fármacos , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/genética
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