Separate and combined effects of DNMT and HDAC inhibitors in treating human multi-drug resistant osteosarcoma HosDXR150 cell line.

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 dysr...

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Autores principales:	Enrico Capobianco, Antonio Mora, Dario La Sala, Annalisa Roberti, Nazar Zaki, Elarbi Badidi, Monia Taranta, Caterina Cinti
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/84351f9cd5a14e0cadcf2ba8d4133153
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spelling	oai:doaj.org-article:84351f9cd5a14e0cadcf2ba8d41331532021-11-18T08:21:51ZSeparate and combined effects of DNMT and HDAC inhibitors in treating human multi-drug resistant osteosarcoma HosDXR150 cell line.1932-620310.1371/journal.pone.0095596https://doaj.org/article/84351f9cd5a14e0cadcf2ba8d41331532014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24756038/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Understanding 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.Enrico CapobiancoAntonio MoraDario La SalaAnnalisa RobertiNazar ZakiElarbi BadidiMonia TarantaCaterina CintiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 4, p e95596 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Enrico Capobianco Antonio Mora Dario La Sala Annalisa Roberti Nazar Zaki Elarbi Badidi Monia Taranta Caterina Cinti Separate and combined effects of DNMT and HDAC inhibitors in treating human multi-drug resistant osteosarcoma HosDXR150 cell line.
description	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.
format	article
author	Enrico Capobianco Antonio Mora Dario La Sala Annalisa Roberti Nazar Zaki Elarbi Badidi Monia Taranta Caterina Cinti
author_facet	Enrico Capobianco Antonio Mora Dario La Sala Annalisa Roberti Nazar Zaki Elarbi Badidi Monia Taranta Caterina Cinti
author_sort	Enrico Capobianco
title	Separate and combined effects of DNMT and HDAC inhibitors in treating human multi-drug resistant osteosarcoma HosDXR150 cell line.
title_short	Separate and combined effects of DNMT and HDAC inhibitors in treating human multi-drug resistant osteosarcoma HosDXR150 cell line.
title_full	Separate and combined effects of DNMT and HDAC inhibitors in treating human multi-drug resistant osteosarcoma HosDXR150 cell line.
title_fullStr	Separate and combined effects of DNMT and HDAC inhibitors in treating human multi-drug resistant osteosarcoma HosDXR150 cell line.
title_full_unstemmed	Separate and combined effects of DNMT and HDAC inhibitors in treating human multi-drug resistant osteosarcoma HosDXR150 cell line.
title_sort	separate and combined effects of dnmt and hdac inhibitors in treating human multi-drug resistant osteosarcoma hosdxr150 cell line.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/84351f9cd5a14e0cadcf2ba8d4133153
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Separate and combined effects of DNMT and HDAC inhibitors in treating human multi-drug resistant osteosarcoma HosDXR150 cell line.

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