title: Separate and combined effects of DNMT and HDAC inhibitors in treating human multi-drug resistant osteosarcoma HosDXR150 cell line.
abstract: 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.
authors.affiliation: Laboratory of Integrative Systems Medicine (LISM), Institute of Clinical Physiology, CNR, Pisa, Italy; Center for Computational Science (CCS), University of Miami, Miami, Florida, United States of America.
authors.forename: Enrico
authors.initials: E
authors.lastname: Capobianco
authors.affiliation: Laboratory of Integrative Systems Medicine (LISM), Institute of Clinical Physiology, CNR, Pisa, Italy; College of Information Technology (CIT), United Arab Emirates University (UAEU), Al Ain, UAE.
authors.forename: Antonio
authors.initials: A
authors.lastname: Mora
authors.affiliation: Institute of Clinical Physiology, Experimental Oncology Unit, CNR, Siena, Italy; Department of Experimental Biomedicine & Clinical Neuroscience, Policlinico Universitario, Palermo, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: La Sala
authors.affiliation: Institute of Clinical Physiology, Experimental Oncology Unit, CNR, Siena, Italy; Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Roberti
authors.affiliation: College of Information Technology (CIT), United Arab Emirates University (UAEU), Al Ain, UAE.
authors.forename: Nazar
authors.initials: N
authors.lastname: Zaki
authors.affiliation: College of Information Technology (CIT), United Arab Emirates University (UAEU), Al Ain, UAE.
authors.forename: Elarbi
authors.initials: E
authors.lastname: Badidi
authors.affiliation: Institute of Clinical Physiology, Experimental Oncology Unit, CNR, Siena, Italy.
authors.forename: Monia
authors.initials: M
authors.lastname: Taranta
authors.affiliation: Institute of Clinical Physiology, Experimental Oncology Unit, CNR, Siena, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Cinti
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019295:Computational Biology; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism*; D015203:Reproducibility of Results; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D004317:Doxorubicin; D015254:DNA Modification Methylases; D006655:Histone Deacetylases
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