title: Antitumor effects of (S)-HDAC42, a phenylbutyrate-derived histone deacetylase inhibitor, in multiple myeloma cells.
abstract: OBJECTIVE
  Epigenetic agents are among the newly targeted therapeutic strategies being studied with intense interest for patients with multiple myeloma. Here, we demonstrate the antitumor activity of a phenylbutyrate-based histone deacetylase (HDAC) inhibitor, (S)-HDAC42, and identify its possible targets in myeloma cells.
  
  
  METHODS
  The antiproliferative effect of (S)-HDAC42 was compared with suberoylanilide hydroxamic acid (SAHA) in three myeloma cell lines, IM-9, RPMI-8226, and U266. Flow cytometry and terminal transferase dUTP nick-end labeling (TUNEL) assay were used to demonstrate the induction of apoptosis by (S)-HDAC42. Moreover, the proposed mechanisms of action, such as modulation of Akt, NF-κB pathway, and cell cycle-related proteins, were investigated by western blotting.
  
  
  RESULTS
  (S)-HDAC42 exhibited four- to sevenfold higher potency relative to SAHA in suppressing myeloma cell viabilities. The apoptotic effect induced by (S)-HDAC42 was through both intrinsic and extrinsic pathways, as evidenced by increased cleavage of caspase-3, caspase-8, and caspase-9 and release of cytochrome c from mitochondria. In addition to HDAC inhibition, (S)-HDAC42 also disturbed signaling pathways governing cell survival, including downregulating Akt phosphorylation and NF-κB signaling. The modulation of cell cycle-related proteins by (S)-HDAC42 suggested its inhibitory effect on cell cycle propagation.
  
  
  CONCLUSIONS
  These data suggest the translational value of (S)-HDAC42 in developing new therapeutic strategies for myeloma, which warrants further investigations.
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Bai
authors.forename: Hany A
authors.initials: HA
authors.lastname: Omar
authors.forename: Chang-Fang
authors.initials: CF
authors.lastname: Chiu
authors.forename: Zeng-Pang
authors.initials: ZP
authors.lastname: Chi
authors.forename: Jing-Lan
authors.initials: JL
authors.lastname: Hu
authors.forename: Jing-Ru
authors.initials: JR
authors.lastname: Weng
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007527:Isoenzymes; D016328:NF-kappa B; D009363:Neoplasm Proteins; C529674:OSU-HDAC42 compound; D010654:Phenylbutyrates; D000077337:Vorinostat; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases