title: HDAC inhibitors and decitabine are highly synergistic and associated with unique gene-expression and epigenetic profiles in models of DLBCL.
abstract: Interactions between histone deacetylase inhibitors (HDACIs) and decitabine were investigated in models of diffuse large B-cell lymphoma (DLBCL). A number of cell lines representing both germinal center B-like and activated B-cell like DLBCL, patient-derived tumor cells and a murine xenograft model were used to study the effects of HDACIs and decitabine in this system. All explored HDACIs in combination with decitabine produced a synergistic effect in growth inhibition and induction of apoptosis in DLBCL cells. This effect was time dependent, mediated via caspase-3 activation, and resulted in increased levels of acetylated histones. Synergy in inducing apoptosis was confirmed in patient-derived primary tumor cells treated with panobinostat and decitabine. Xenografting experiments confirmed the in vitro activity and tolerability of the combination. We analyzed the molecular basis for this synergistic effect by evaluating gene-expression and methylation patterns using microarrays, with validation by bisulfite sequencing. These analyses revealed differentially expressed genes and networks identified by each of the single treatment conditions and by the combination therapy to be unique with few overlapping genes. Among the genes uniquely altered by the combination of panobinostat and decitabine were VHL, TCEB1, WT1, and DIRAS3.
authors.affiliation: New York University Cancer Institute, New York University Langone Medical Center, 522 First Avenue, New York, NY 10016, USA.
authors.forename: Matko
authors.initials: M
authors.lastname: Kalac
authors.forename: Luigi
authors.initials: L
authors.lastname: Scotto
authors.forename: Enrica
authors.initials: E
authors.lastname: Marchi
authors.forename: Jennifer
authors.initials: J
authors.lastname: Amengual
authors.forename: Venkatraman E
authors.initials: VE
authors.lastname: Seshan
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.forename: Netha
authors.initials: N
authors.lastname: Ulahannan
authors.forename: Violetta V
authors.initials: VV
authors.lastname: Leshchenko
authors.forename: Alexis M
authors.initials: AM
authors.lastname: Temkin
authors.forename: Samir
authors.initials: S
authors.lastname: Parekh
authors.forename: Benjamin
authors.initials: B
authors.lastname: Tycko
authors.forename: Owen A
authors.initials: OA
authors.lastname: O'Connor
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004357:Drug Synergism; D044127:Epigenesis, Genetic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D000077767:Panobinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D000077209:Decitabine; D000077767:Panobinostat; D001374:Azacitidine