title: Effect of histone deacetylase inhibitors trichostatin A and valproic acid on etoposide-induced apoptosis in leukemia cells.
abstract: BACKGROUND
  Histone deacetylase inhibitors (HDACi) have been extensively studied as potential candidates for treatment of various malignancies, including leukemia, since they not only induce growth inhibition, cell cycle arrest and apoptosis of cancer cells, but can also increase the sensitivity of cancer cells to chemotherapeutic drugs. The aim of this study was to investigate the effect of two HDACi, trichostatin A (TSA) and valproic acid (VPA), on etoposide-induced apoptosis in human leukemia cell lines.
  
  
  METHODS
  Viability, apoptosis rate, caspase activity, mitochondrial membrane potential and expression of BCL2 mRNA were assessed in HL60 and U937 cell lines treated with 250 nM TSA or 1.25 mM VPA alone or followed by 5 μM etoposide.
  
  
  RESULTS
  Preincubation of HL60 cells with TSA or VPA significantly potentiated etoposide-induced cytotoxicity and apoptosis, which was associated with activation of caspases and loss of mitochondrial membrane potential. Similar effects were not observed in U937 cells. Expression of BCL2 mRNA was strongly down-regulated after treatment of cells with HDACi alone but did not show additive effect with etoposide.
  
  
  CONCLUSIONS
  Combination of HDACi with etoposide can have a synergistic effect on increased apoptosis in leukemia cells but this effect depends on the cancer cell type and other factors such as the concentration of drugs and the administration schedule.
authors: Department of Histology, Jagiellonian University Medical College, Kopernika 7, PL-31034 Krakow, Poland. ejasek@cm-uj.krakow.pl
authors: Ewa
authors: E
authors: Jasek
authors: Grzegorz J
authors: GJ
authors: Lis
authors: Malgorzata
authors: M
authors: Jasinska
authors: Halina
authors: H
authors: Jurkowska
authors: Jan A
authors: JA
authors: Litwin
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage / Q000494:pharmacology*; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020298:U937 Cells; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; C012589:trichostatin A; D014635:Valproic Acid; D005047:Etoposide; D053148:Caspase 3; D053179:Caspase 7