title: The histone deacetylase inhibitor entinostat (SNDX-275) induces apoptosis in Hodgkin lymphoma cells and synergizes with Bcl-2 family inhibitors.
abstract: OBJECTIVE
  Based on promising in vitro and in vivo activity of several histone deacetylase inhibitors in Hodgkin lymphoma (HL), we investigated SNDX-275, an oral class 1 isoform-selective histone deacetylase inhibitors in HL-derived cell lines.
  
  
  METHODS
  Proliferation and cell death were examined by MTS assay, Annexin V/propidium iodide, and fluorescence-activated cell sorting analysis. Gene and protein expression were measured by reverse transcriptase polymerase chain reaction, Western blotting, and immunohistochemical analysis. A multiplex assay was used to determine cytokines and chemokines.
  
  
  RESULTS
  SNDX-275 induced cell death in a dose- and time-dependent manner with an IC(50) at the sub- and lower micromolar range at 72 hours. At the molecular level, SNDX-275 increased histone H3 acetylation, upregulated p21 expression, and activated the intrinsic apoptosis pathway by downregulating the X-linked inhibitor of apoptosis protein. SNDX-275 downregulated expression of antiapoptotic Bcl-2 and Bcl-xL proteins without altering Mcl-1 or Bax levels. Combination studies demonstrated that two Bcl-2 inhibitors (ABT-737 and obatoclax) significantly enhanced the effect of SNDX-275. SNDX-275 modulated the level of several cytokines and chemokines, including interleukin-12 p40-70, interferon-inducible protein-10, RANTES (regulated on activation, normal T expressed and secreted), interleukin-13, interleukin-4, and thymus and activation-regulated chemokine and variably induced the cancer/testis antigen expression of MAGE-A4 and survivin in HL cell lines.
  
  
  CONCLUSIONS
  SNDX-275 has antiproliferative activity in HL cell lines, involving several mechanisms: induction of apoptosis, regulation of cytokines and chemokines, and alteration of cancer/testis antigens. Clinical investigation of SNDX-275 alone or in combination with Bcl-2 inhibitors is warranted in patients with HL. Phase 2 studies with SNDX-275 in HL are ongoing, and future clinical studies should investigate combinations with SNDX-275.
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, USA.
authors.forename: Adám
authors.initials: A
authors.lastname: Jóna
authors.forename: Noor
authors.initials: N
authors.lastname: Khaskhely
authors.forename: Daniela
authors.initials: D
authors.lastname: Buglio
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Shafer
authors.forename: Enrico
authors.initials: E
authors.lastname: Derenzini
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Bollard
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.forename: Arpád
authors.initials: A
authors.lastname: Illés
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ji
authors.forename: Anas
authors.initials: A
authors.lastname: Younes
mesh_terms: D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D001549:Benzamides / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006689:Hodgkin Disease / Q000473:pathology*; D006801:Humans; D007211:Indoles; D008228:Lymphoma, Non-Hodgkin / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis / Q000235:genetics; D000093542:Gemcitabine
chemical_list: C501332:ABT-737; D051017:Apoptosis Regulatory Proteins; D001549:Benzamides; D001713:Biphenyl Compounds; D001897:Boronic Acids; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D007211:Indoles; D009363:Neoplasm Proteins; D009596:Nitrophenols; D010879:Piperazines; D011719:Pyrazines; D011725:Pyridines; D011758:Pyrroles; D013449:Sulfonamides; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D003841:Deoxycytidine; C118739:entinostat; D000069286:Bortezomib; C520962:obatoclax; D000093542:Gemcitabine