RESUMO
The indisputable role of epigenetics in cancer and the fact that epigenetic alterations can be reversed have favoured development of epigenetic drugs. In this study, we design and synthesize potent novel, selective and reversible chemical probes that simultaneously inhibit the G9a and DNMTs methyltransferase activity. In vitro treatment of haematological neoplasia (acute myeloid leukaemia-AML, acute lymphoblastic leukaemia-ALL and diffuse large B-cell lymphoma-DLBCL) with the lead compound CM-272, inhibits cell proliferation and promotes apoptosis, inducing interferon-stimulated genes and immunogenic cell death. CM-272 significantly prolongs survival of AML, ALL and DLBCL xenogeneic models. Our results represent the discovery of first-in-class dual inhibitors of G9a/DNMTs and establish this chemical series as a promising therapeutic tool for unmet needs in haematological tumours.
Assuntos
Antineoplásicos/farmacologia , Metilases de Modificação do DNA/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Neoplasias Hematológicas/tratamento farmacológico , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Cristalografia por Raios X , Metilases de Modificação do DNA/química , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Feminino , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Antígenos de Histocompatibilidade/química , Antígenos de Histocompatibilidade/genética , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/química , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Interferons/imunologia , Interferons/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos , Simulação de Acoplamento Molecular , Análise de Sobrevida , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Yin Yang 1 (YY1), a multifunctional transcription factor, has been shown to be involved in the pathogenesis of several cancer types. However, its role in hematological malignancies has not yet been fully investigated. In the present study, using computational methods, we showed that YY1 transcript levels were significantly increased in the high-grade lymphomas, including Burkitt's lymphoma and diffuse large B-cell lymphoma (DLBCL), compared with those of both low-grade lymphomas and normal B-cells. The significant increase in gene expression resulted in a significant increase also at protein level in three NHL cell lines. The association of YY1 expression with some clinical-pathological features in DLBCL showed a positive correlation between a high level of YY1 mRNA and high levels of BCL-6 protein. Moreover, by analyzing the large series of DLBCL in the Hummel dataset, we identified the transcription factor PAX-5 among the top 50 genes positively correlated with YY1. These findings are also supported by the biological network analysis in which the top network, with the highest score, associated with YY1 expression levels in DLBCL is cellular movement, hematological system development and function, and immune response. overall these data suggest that YY1 is involved in B cells transformation which gives rise to high-grade lymphomas through a dysregulation in the normal development of B cells affecting cell cycle and cellular motility.
Assuntos
Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Fator de Transcrição YY1/genética , Western Blotting , Linhagem Celular Tumoral , Progressão da Doença , Redes Reguladoras de Genes , Humanos , Software , Fator de Transcrição YY1/metabolismoRESUMO
The Yin Yang 1 (YY1) transcription factor has a pivotal role in normal biological processes such as development, differentiation, replication and cell proliferation exerting its effects on a huge number of genes involved in these processes. Mechanisms of YY1 action are related to its ability to initiate, activate, or repress transcription depending upon the context in which it binds. The role of YY1 played in cancer has been recently explored. This article summarizes the most relevant studies focused on YY1 regulation and dwells on the way how its overexpression may affect the clinical behavior of several cancer types. Furthermore, the contribution of the upregulation of YY1 exerted in response to therapeutic-induced apoptosis is discussed.
Assuntos
Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Fator de Transcrição YY1/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lesões Pré-Cancerosas/tratamento farmacológico , Lesões Pré-Cancerosas/genética , Fator de Transcrição YY1/química , Fator de Transcrição YY1/genéticaRESUMO
Extradural motor cortex stimulation was introduced in 1989 for control of central pain. In recent years this has been found useful in several patients with movement disorders. This paper attempts to bring together all the relevant literature, discuss mechanisms and lay out guidelines for future research and clinical applications.
Assuntos
Terapia por Estimulação Elétrica/métodos , Córtex Motor/fisiologia , Transtornos dos Movimentos/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Dura-Máter , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Motor cortex stimulation is a minimally invasive surgical procedure used for pain control. The authors report their results treating two patients with typical Parkinson disease. Unilateral motor cortex stimulation proved to be beneficial bilaterally. Motor cortex stimulation may represent a cost-effective alternative to deep brain stimulation.