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.
Clin Cancer Res ; 17(24): 7605-13, 2011 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-22010212

RESUMO

PURPOSE: Sensitivity of tumor cells toward chemotherapy mainly determines the prognosis of patients suffering from acute lymphoblastic leukemia (ALL); nevertheless, underlying mechanisms regulating chemosensitivity remain poorly understood. Here, we aimed at characterizing the role of caspase-8 for chemosensitivity of B- and T-ALL cells. EXPERIMENTAL DESIGN: Primary tumor cells from children with ALL were evaluated for expression levels of the caspase-8 protein, were amplified in nonobese diabetic/severe combined immunodeficient mice, transfected with siRNA, and evaluated for their chemosensitivity in vitro. RESULTS: Effective cell death in B- and T-ALL cells depended on the presence of caspase-8 for the majority of cytotoxic drugs routinely used in antileukemia treatment. Caspase-8 was activated independently from extrinsic apoptosis signaling. Accordingly in primary ALL cells, the expression level of caspase-8 protein correlated with cell death sensitivity toward defined cytotoxic drugs in vitro. In the subgroup of primary ALL cells, with low expression of caspase-8, methotrexate (MTX) upregulated the expression of caspase-8 mediated by the transcription factor p53, suggesting epigenetic silencing of caspase-8. RNA interference in patient-derived B- and T-ALL cells revealed that effective cell death induction by most routine drug combinations involving MTX depended on the presence of caspase-8. CONCLUSION: Our results indicate that caspase-8 is crucial for the high antileukemic efficiency of numerous routine cytotoxic drugs. Reexpression of epigenetically downregulated caspase-8 represents a promising approach to increase efficiency of antileukemic therapy.


Assuntos
Antineoplásicos/farmacologia , Caspase 8/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Caspase 8/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Criança , Citarabina/farmacologia , Dexametasona/farmacologia , Doxorrubicina/farmacologia , Ativação Enzimática/efeitos dos fármacos , Humanos , Células Jurkat , Metotrexato/farmacologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Interferência de RNA , Tioguanina/farmacologia , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Cancer Cell ; 19(2): 206-17, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21295523

RESUMO

We investigated the engraftment properties and impact on patient outcome of 50 pediatric acute lymphoblastic leukemia (ALL) samples transplanted into NOD/SCID mice. Time to leukemia (TTL) was determined for each patient sample engrafted as weeks from transplant to overt leukemia. Short TTL was strongly associated with high risk for early relapse, identifying an independent prognostic factor. This high-risk phenotype is reflected by a gene signature that upon validation in an independent patient cohort (n = 197) identified a high-risk cluster of patients with early relapse. Furthermore, the signature points to independent pathways, including mTOR, involved in cell growth and apoptosis. The pathways identified can directly be targeted, thereby offering additional treatment approaches for these high-risk patients.


Assuntos
Perfilação da Expressão Gênica , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Animais , Apoptose/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Recidiva , Análise de Sobrevida , Transplante Heterólogo
3.
Blood ; 111(5): 2899-903, 2008 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-18083847

RESUMO

Recently we reported that intact apoptosis signaling is indicative of favorable outcome in childhood acute lymphoblastic leukemia. Here we addressed this issue in 45 pediatric acute myeloid leukemia patients analyzing 2 core apoptogenic events: cytochrome c release and caspase-3 activation. In patients with good prognosis cytochrome c release was clearly found to be caspasedependent and correlated with activated caspase-3, indicating that activation of initiator or amplifier caspases such as caspase-8 together with an intact apoptosome function are elementary for favorable outcome. The functional integrity of this apoptogenic checkpoint is reflected by the parameter caspase-dependent cytochrome c-related activation of caspase-3 (CRAC(dep)). Patients with positive CRAC(dep) values (intact signaling) exhibited superior survival compared with CRAC(dep) negative patients (deficient signaling). Thus, the propensity to undergo apoptosis of leukemia cells is an important feature for favorable treatment outcome and may serve as an additional stratification tool for pediatric AML patients. This trial was registered at www.ClinicalTrials.gov as #NCT00111345.


Assuntos
Apoptose , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Transdução de Sinais , Caspase 3/metabolismo , Criança , Citocromos c/metabolismo , Intervalo Livre de Doença , Ativação Enzimática , Humanos , Leucemia Mieloide Aguda/enzimologia , Indução de Remissão , Fatores de Risco , Resultado do Tratamento
4.
Blood ; 107(11): 4524-31, 2006 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-16467206

RESUMO

Deficient activation of apoptosis signaling pathways may be responsible for treatment failure in acute leukemia. Here, we address the impact of intact apoptosis signaling in 78 patients with pediatric precursor B-cell acute lymphoblastic leukemia (ALL) by analysis of 2 key apoptogenic events: caspase-3 activation and cytochrome c release in leukemia cells cultured in vitro. Both events correlated only in the group of patients who had a good response and patients in continuous remission, suggesting that intact apoptosis signaling is a characteristic for favorable outcome. By combining both parameters, we identified a novel indicator, cytochrome c-related activation of caspase-3 (CRAC). CRAC directly connects the extent of caspase-3 activation to cytochrome c release in single cells in an individual patient sample. In CRAC-positive patients, indicating proficient apoptosis signaling, the number of persisting leukemia cells on day 15 was significantly lower than in the CRAC-negative patient group (n = 27, mean 6.0% versus n = 36, mean 22.6%; P = .003). At a median follow-up of 31 months, disease-free survival was 84 months (95% CI = 76 to 91 months) and 66 months (95% CI = 52 to 80 months) for patients with positive and negative CRAC, respectively (P = .019). CRAC may serve as a functionally defined risk factor for treatment stratification.


Assuntos
Caspases/metabolismo , Citocromos c/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adolescente , Apoptose , Caspase 3 , Contagem de Células , Criança , Pré-Escolar , Citometria de Fluxo , Humanos , Lactente , Prognóstico , Recidiva , Medição de Risco , Resultado do Tratamento
5.
Oncogene ; 24(14): 2421-9, 2005 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-15735742

RESUMO

Regulation of sensitivity or resistance for apoptosis by death receptor ligand systems is a key control mechanism in the hematopoietic system. Dysfunctional or deregulated apoptosis can potentially contribute to the development of immune deficiencies, autoimmune diseases, and leukemia. Control of homeostasis starts at the level of hematopoietic stem cells (HSC). To this end, we found that CD34+ hematopoietic progenitor cells are constitutively resistant to CD95-mediated apoptosis and cannot be sensitized during short-term culture to death receptor-mediated apoptosis by cytokines. Detailed analysis of the death machinery revealed that CD34+ cells do not express caspase-8a/b, a crucial constituent of the death-inducing signaling complex (DISC) of death receptors. Instead, we found a smaller splice variant termed caspase-8L to be present in HSC. Forced expression of caspase-8L using a recombinant lentiviral vector was able to protect hematopoietic cells from death receptor-induced apoptosis even in the presence of caspase-8a/b. Furthermore, we found that caspase-8L is recruited to the DISC after CD95 triggering, thereby preventing CD95 from connecting to the caspase cascade. These results demonstrate an antiapoptotic function of caspase-8L and suggest a critical role as apoptosis regulator in HSC. Similar to CD34+ HSC, stem cell-derived leukemic blasts from AML(M0) patients only expressed caspase-8L. Additionally we found, caspase-8L expression in several AML and ALL samples. Thus, caspase-8L expression might explain constitutive resistance to CD95-mediated apoptosis in CD34+ progenitor cells and might participate in the development of stem cell-derived and other leukemias by providing protection from regulatory apoptosis.


Assuntos
Antígenos CD34/imunologia , Antígenos CD/fisiologia , Apoptose/fisiologia , Caspases/metabolismo , Células-Tronco Hematopoéticas/citologia , Lectinas Tipo C/fisiologia , Leucemia/patologia , Caspase 8 , Células-Tronco Hematopoéticas/imunologia , Humanos , Subfamília D de Receptores Semelhantes a Lectina de Células NK
6.
Cancer Immunol Immunother ; 54(7): 655-62, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15703961

RESUMO

Doxorubicin is a commonly used cytotoxic drug for effective treatment of both solid tumors and leukemias, which may cause severe cardiac adverse effects leading to heart failure. In certain tumor cells, doxorubicin-induced cell death is mediated by death receptors such as CD95/Apo-1/Fas. Here we studied the role of death receptors for doxorubicin-induced cell death in primary neonatal rat cardiomyocytes and the embryonic cardiomyocytic cell line H9c2.1. Doxorubicin-induced cell death of cardiomyocytes was associated with cleavage of caspases 3 and 8, a drop in mitochondrial transmembrane potential, and release of cytochrome c. Doxorubicin-treated cardiomyocytes secreted death-inducing ligands into the culture supernatant, but remained resistant toward cell death induction by death receptor triggering. In contrast to the chelator dexrazoxane, blockade of death receptor signaling by stable overexpression of transdominant negative adapter molecule FADD did not inhibit doxorubicin-induced cell death. Our data suggest that cultured cardiomyocytes secrete death-inducing ligands, but undergo death receptor-independent cell death upon exposure to doxorubicin.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Doxorrubicina/farmacologia , Glicoproteínas de Membrana/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Receptor fas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Animais Recém-Nascidos , Caspase 3 , Caspase 8 , Caspases/metabolismo , Células Cultivadas , Citocromos c/metabolismo , Proteína Ligante Fas , Proteína de Domínio de Morte Associada a Fas , Genes Dominantes , Humanos , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Miócitos Cardíacos/metabolismo , Ratos
7.
Semin Cancer Biol ; 13(2): 149-58, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12654258

RESUMO

Apoptosis, the cell's intrinsic death program, plays a critical role in the regulation of tissue homeostasis, especially in cell systems with a high turnover rate such as hematopoietic cells. Imbalances between proliferation and cell death may result in premature death, uncontrolled polyclonal or monoclonal expansion or tumor formation. Also, cytotoxic therapy and immunotherapy of leukemia and lymphoma predominantly mediates cell death through induction of apoptosis. Understanding the molecular events by which tumor cells evade apoptotic deletion and which induce apoptosis by cytotoxic therapies, have provided a paradigm to link normal growth control, malignant transformation and response to therapy.


Assuntos
Apoptose/fisiologia , Doenças Hematológicas/patologia , Animais , Transformação Celular Neoplásica , Humanos , Leucemia/patologia , Linfoma/patologia , Receptor fas/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...