title: Superior efficacy of a combined epigenetic therapy against human mantle cell lymphoma cells.
abstract: OBJECTIVE
  A deregulated epigenome contributes to the transformed phenotype of mantle cell lymphoma (MCL). This involves activity of the polycomb repressive complex (PRC) 2, containing three core proteins, EZH2, SUZ12, and EED, in which the SET domain of EZH2 mediates the histone methyltransferase activity. We determined the effects of 3-deazaneplanocin A (DZNep), an S-adenosylhomocysteine hydrolase inhibitor, and/or pan-histone deacetylase inhibitor panobinostat (PS) on cultured and primary MCL cells.
  
  
  METHODS
  Following treatment with DZNep and/or PS, apoptosis and the levels and activity of EZH2 and PRC2 proteins in cultured and primary MCL cells were determined.
  
  
  RESULTS
  Treatment with DZNep depleted EZH2, SUZ12, and 3MeK27H3 in the cultured human MCL cells. DZNep also increased expression of p21, p27, and FBXO32, whereas it depleted Cyclin D1 and Cyclin E1 levels in MCL cells. In addition, DZNep treatment induced cell-cycle arrest and apoptosis in cultured and primary MCL cells. Furthermore, as compared with treatment with each agent alone, cotreatment with DZNep and PS caused greater depletion of EZH2, SUZ12, 3MeK27H3, and Cyclin D1 levels, whereas it induced greater expression of FBXO32, p16, p21, and p27. Combined treatment with DZNep and PS synergistically induced apoptosis of cultured and primary MCL cells while relatively sparing normal CD34 + cells. Cotreatment with DZNep and PS also caused significantly greater inhibition of tumor growth of JeKo-1 xenografts in NOD/SCID mice.
  
  
  CONCLUSIONS
  These preclinical in vitro and in vivo findings show that cotreatment with DZNep and PS is an active combined epigenetic therapy worthy of further in vivo testing against MCL.
authors.affiliation: University of Kansas Cancer Center, Kansas City, Kansas 66160, USA.
authors.forename: Warren
authors.initials: W
authors.lastname: Fiskus
authors.forename: Rekha
authors.initials: R
authors.lastname: Rao
authors.forename: Ramesh
authors.initials: R
authors.lastname: Balusu
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Ganguly
authors.forename: Jianguo
authors.initials: J
authors.lastname: Tao
authors.forename: Eduardo
authors.initials: E
authors.lastname: Sotomayor
authors.forename: Uma
authors.initials: U
authors.lastname: Mudunuru
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Smith
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Hembruff
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: Kapil
authors.initials: K
authors.lastname: Bhalla
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins; D000077767:Panobinostat; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D009124:Muscle Proteins; D009363:Neoplasm Proteins; C430461:SUZ12 protein, human; D014157:Transcription Factors; C048460:3-deazaneplanocin; D000077767:Panobinostat; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C440907:FBXO32 protein, human; D044843:SKP Cullin F-Box Protein Ligases; D000241:Adenosine