Separate and Combined Effects of DNMT and HDAC Inhibitors in Treating Human Multi-Drug Resistant Osteosarcoma HosDXR150 Cell LineReportar como inadecuado




Separate and Combined Effects of DNMT and HDAC Inhibitors in Treating Human Multi-Drug Resistant Osteosarcoma HosDXR150 Cell Line - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

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.



Autor: Enrico Capobianco, Antonio Mora, Dario La Sala, Annalisa Roberti, Nazar Zaki, Elarbi Badidi, Monia Taranta, Caterina Cinti

Fuente: http://plos.srce.hr/



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