RESUMO
PURPOSE: Glioblastoma multiforme (GBM) is the most common and aggressive malignant type of brain tumor. Despite advances in diagnosis and therapy, the prognosis of patients with GBM has remained dismal. Multidrug resistance and high recurrence are two of the major challenges in successfully treating brain tumors. IKBKE (inhibitor of nuclear factor kappa-B kinase subunit epsilon) is a major oncogenic protein in tumors and can inhibit glioblastoma cell proliferation, migration, and tumorigenesis. Our study aimed to investigate the mechanism of IKBKE enhancing the resistance of glioma cells to temozolomide. METHODS: For the in vitro experiments, LN18 and U118 glioblastoma cells were treated with a combination of sh/oe-IKBKE lentivirus and TMZ. Cell proliferation was determined by the EdU assay and colony formation assays. Apoptosis was analyzed by the TUNEL assay. In vivo, LN18 NC and LN18 sh-IKBKE cells were implanted into the cerebrums of nude mice to detect the effect of combination therapy. The protein and mRNA levels were assayed by western blot, immunohistochemistry, and qRT-PCR. RESULTS: In this study, we demonstrated that IKBKE enhances the resistance of glioblastoma cells to temozolomide (TMZ) by activating the AKT/NF-κB signaling pathway to upregulate the expression of the DNA repair enzyme o6-methylguanine-dna methyltransferase (MGMT). In glioblastoma cells, IKBKE knockdown enhances apoptosis and suppresses cell proliferation, clone formation, and tumor development in vivo induced by TMZ. However, overexpression of IKBKE reduces the effects of TMZ. CONCLUSION: Our studies suggest that inhibition of IKBKE can enhance the therapeutic effect of TMZ on GBM in vitro and in vivo, providing new research directions and therapeutic targets for the treatment of GBM.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Glioblastoma/tratamento farmacológico , Quinase I-kappa B/metabolismo , Temozolomida/farmacologia , Proteínas Supressoras de Tumor/metabolismo , Animais , Apoptose/fisiologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Resistência a Múltiplos Medicamentos/fisiologia , Feminino , Técnicas de Silenciamento de Genes , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Quinase I-kappa B/antagonistas & inibidores , Quinase I-kappa B/genética , Quinase I-kappa B/farmacologia , Lentivirus , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/farmacologia , Transplante de Neoplasias , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/análise , Transdução Genética/métodos , Regulação para Cima , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
To assess the natural history of the immune defect in DiGeorge anomaly, we reviewed serial immunologic studies in 18 patients. The diagnosis was made with criteria based on the concept of the DiGeorge anomaly as a field defect. Initial or early follow-up laboratory examination suggested moderate to normal T cell function in 14 patients. None of these patients have lost T cell capability; they have never had infections characteristic of T cell deficiency. Four patients had clinical and laboratory evidence of profound immunodeficiency. A decreased number of CD4+ cells (less than 400/microliters) and a decrease in phytohemagglutinin responsiveness (stimulation index less than 10) may be useful in discriminating patients with immunodeficiency; absolute lymphocyte count and immunoglobulin values were not informative. At the time of surgery, the thymus was not found in 11 of 14 patients; however, only two of these patients had immunodeficiency. Patients with a persistently low number of CD4+ cells and decreased phytohemagglutinin response are candidates for immunologic reconstitution.
Assuntos
Doenças Autoimunes/imunologia , Síndrome de DiGeorge/imunologia , Síndromes de Imunodeficiência/imunologia , Envelhecimento/imunologia , Pré-Escolar , Reações Falso-Positivas , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Contagem de Leucócitos , Masculino , Linfócitos TRESUMO
Two siblings with a congenital syndrome of secretory diarrhea and seizures developed progressive skin rash, alopecia, and mucocutaneous candidiasis while receiving biotin-free total parenteral nutrition. Abnormally low urinary biotin excretion was associated with these clinical findings, but the serum concentration of biotin was within the normal range. There was also increased urinary excretion of lactic acid, 3-hydroxyisovaleric acid, 3-hydroxypropionic acid, and 3-methylcrotonylglycine. The younger of the two children subsequently died with severe metabolic acidosis. In the oder sibling, intravenous treatment with biotin (200 micrograms/day) resulted in resolution of the organic aciduria. A larger dose (10 mg/day) appeared to be required for rapid improvement in the skin lesions. These cases suggest that clinically significant biotin deficiency can occur in patients with chronic diarrhea receiving biotin-free total parenteral nutrition.
Assuntos
Biotina/uso terapêutico , Carbono-Carbono Ligases , Carboxiliases/deficiência , Diarreia Infantil/terapia , Ligases/deficiência , Nutrição Parenteral Total/efeitos adversos , Nutrição Parenteral/efeitos adversos , Biotina/metabolismo , Pré-Escolar , Diarreia Infantil/genética , Diarreia Infantil/imunologia , Feminino , Humanos , Masculino , Metilmalonil-CoA Descarboxilase , Propionatos/deficiência , Convulsões/complicações , Convulsões/genética , Convulsões/terapiaAssuntos
Macrófagos , Monócitos , Evolução Biológica , Membrana Celular/ultraestrutura , Quimiotaxia , Humanos , Imunidade Celular , Síndromes de Imunodeficiência/patologia , Fatores Inibidores da Migração de Macrófagos/farmacologia , Macrófagos/fisiologia , Macrófagos/ultraestrutura , Monócitos/fisiologia , Monócitos/ultraestrutura , Neoplasias/imunologia , Neoplasias/patologia , Fagocitose , Filogenia , Receptores de Droga , Linfócitos T/imunologiaRESUMO
An infant with severe combined immunodeficiency had normal numbers of lymphocytes which bore E rosette and surface Ig markers in an appropriate distribution. However, only minimal responsivity to in vitro stimulation by mitogens and allogenic cells, and none to antigens could be elicited; functional antibody responses were also nil, except to cytomegalovirus. Intrauterine-acquired cytomegalovirus may have caused his immune dysfunction, although the possibility of a postnatal infection cannot be excluded. Therapy with transfer factor and thymus transplantation was unsucessful in restoring immunity and may have aggravated a pre-existing monoclonal gammopathy. It is possible that the monoclonal protein was derived from B-cells transplacentally received from the patients mother.
Assuntos
Formação de Anticorpos , Infecções por Citomegalovirus/imunologia , Hipergamaglobulinemia/complicações , Imunoglobulina G , Síndromes de Imunodeficiência/complicações , Antígenos/administração & dosagem , Doença Crônica , Infecções por Citomegalovirus/complicações , Testes Imunológicos de Citotoxicidade , Eritrócitos/imunologia , Humanos , Hipergamaglobulinemia/imunologia , Reação de Imunoaderência , Síndromes de Imunodeficiência/imunologia , Lactente , Recém-Nascido , Linfócitos/imunologia , Mitógenos/imunologia , Testes CutâneosRESUMO
Biopsies of the proximal small bowel were obtained in four children with impairment of cell-mediated immunity, chronic diarrhia, and malabsorption; one child had an isolated T cell defect and three had significant B and T cell defects. All of them had malabsorption and, in addition to alterations of the small bowel epithelium, large vacuolated macrophages were seen in the lamina propria in all biopsies. Electron microscopy demonstrated lipid and patches of small pleomorphic inclusions within the macrophages. Since large vacuolated macrophages have also been described in Whipple's disease and chronic granulomatous disease, we suggest the possibility of a common thread of defective host defense and gastrointestinal malfunction in these three conditions.