RESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Metilasas de Modificación del ADN/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Neoplasias Hematológicas/tratamiento farmacológico , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/genética , Apoptosis/inmunología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Cristalografía por Rayos X , Metilasas de Modificación del ADN/química , Metilasas de Modificación del ADN/genética , Metilasas de Modificación del ADN/metabolismo , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Epigénesis Genética/efectos de los fármacos , Femenino , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/mortalidad , Antígenos de Histocompatibilidad/química , Antígenos de Histocompatibilidad/genética , Antígenos de Histocompatibilidad/metabolismo , N-Metiltransferasa de Histona-Lisina/química , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Interferones/inmunología , Interferones/metabolismo , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos , Simulación del Acoplamiento Molecular , Análisis de Supervivencia , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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.
Asunto(s)
Transformación Celular Neoplásica/genética , Regulación Neoplásica de la Expresión Génica , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Factor de Transcripción YY1/genética , Western Blotting , Línea Celular Tumoral , Progresión de la Enfermedad , Redes Reguladoras de Genes , Humanos , Programas Informáticos , Factor de Transcripción YY1/metabolismoRESUMEN
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.
Asunto(s)
Lesiones Precancerosas/metabolismo , Lesiones Precancerosas/patología , Factor de Transcripción YY1/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Lesiones Precancerosas/tratamiento farmacológico , Lesiones Precancerosas/genética , Factor de Transcripción YY1/química , Factor de Transcripción YY1/genéticaRESUMEN
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.
Asunto(s)
Terapia por Estimulación Eléctrica/métodos , Corteza Motora/fisiología , Trastornos del Movimiento/terapia , Adulto , Anciano , Anciano de 80 o más Años , Duramadre , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
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.