RESUMEN
Understanding the molecular mechanisms underlying multi-drug resistance (MDR) is one of the major challenges in current cancer research. A phenomenon which is common to both intrinsic and acquired resistance, is the aberrant alteration of gene expression in drug-resistant cancers. Although such dysregulation depends on many possible causes, an epigenetic characterization is considered a main driver. Recent studies have suggested a direct role for epigenetic inactivation of genes in determining tumor chemo-sensitivity. We investigated the effects of the inhibition of DNA methyltransferase (DNMT) and hystone deacethylase (HDAC), considered to reverse the epigenetic aberrations and lead to the re-expression of de novo methylated genes in MDR osteosarcoma (OS) cells. Based on our analysis of the HosDXR150 cell line, we found that in order to reduce cell proliferation, co-treatment of MDR OS cells with DNMT (5-Aza-dC, DAC) and HDAC (Trichostatin A, TSA) inhibitors is more effective than relying on each treatment alone. In re-expressing epigenetically silenced genes induced by treatments, a very specific regulation takes place which suggests that methylation and de-acetylation have occurred either separately or simultaneously to determine MDR OS phenotype. In particular, functional relationships have been reported after measuring differential gene expression, indicating that MDR OS cells acquired growth and survival advantage by simultaneous epigenetic inactivation of both multiple p53-independent apoptotic signals and osteoblast differentiation pathways. Furthermore, co-treatment results more efficient in inducing the re-expression of some main pathways according to the computed enrichment, thus emphasizing its potential towards representing an effective therapeutic option for MDR OS.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Óseas/metabolismo , Metilasas de Modificación del ADN/antagonistas & inhibidores , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Osteosarcoma/metabolismo , Neoplasias Óseas/genética , Línea Celular Tumoral , Biología Computacional , Relación Dosis-Respuesta a Droga , Doxorrubicina/farmacología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Osteosarcoma/genética , Reproducibilidad de los Resultados , Transducción de Señal , Factores de TiempoRESUMEN
BACKGROUND: Sequence data analyses such as gene identification, structure modeling or phylogenetic tree inference involve a variety of bioinformatics software tools. Due to the heterogeneity of bioinformatics tools in usage and data requirements, scientists spend much effort on technical issues including data format, storage and management of input and output, and memorization of numerous parameters and multi-step analysis procedures. RESULTS: In this paper, we present the design and implementation of AnaBench, an interactive, Web-based bioinformatics Analysis workBench allowing streamlined data analysis. Our philosophy was to minimize the technical effort not only for the scientist who uses this environment to analyze data, but also for the administrator who manages and maintains the workbench. With new bioinformatics tools published daily, AnaBench permits easy incorporation of additional tools. This flexibility is achieved by employing a three-tier distributed architecture and recent technologies including CORBA middleware, Java, JDBC, and JSP. A CORBA server permits transparent access to a workbench management database, which stores information about the users, their data, as well as the description of all bioinformatics applications that can be launched from the workbench. CONCLUSION: AnaBench is an efficient and intuitive interactive bioinformatics environment, which offers scientists application-driven, data-driven and protocol-driven analysis approaches. The prototype of AnaBench, managed by a team at the Université de Montréal, is accessible on-line at: http://malawimonas.bcm.umontreal.ca:8091/anabench. Please contact the authors for details about setting up a local-network AnaBench site elsewhere.
Asunto(s)
Internet , Análisis de Secuencia/métodos , Programas Informáticos , Biología Computacional/métodos , Biología Computacional/tendencias , Gráficos por Computador/tendencias , Sistemas de Administración de Bases de Datos/tendencias , Bases de Datos Genéticas/tendencias , Humanos , Ácidos Nucleicos/genética , Filogenia , Lenguajes de Programación , Proteínas/genética , Análisis de Secuencia/tendencias , Diseño de Software , Interfaz Usuario-ComputadorRESUMEN
GOBASE is a relational database containing integrated sequence, RNA secondary structure and biochemical and taxonomic information about organelles. GOBASE release 6 (summer 2002) contains over 130 000 mitochondrial sequences, an increase of 37% over the previous release, and more than 30 000 chloroplast sequences in a new auxiliary database. To handle this flood of new data, we have designed and implemented GOpop, a Java system for population and verification of the database. We have also implemented a more powerful and flexible user interface using the PHP programming language. http://megasun.bch.umontreal.ca/gobase/gobase.html.