title: Inhibitors of poly ADP-ribose polymerase (PARP) induce apoptosis of myeloid leukemic cells: potential for therapy of myeloid leukemia and myelodysplastic syndromes.
abstract: Background Aberrant or impaired repair of double-strand DNA breaks is a common feature of de novo acute myeloid leukemia and myelodysplastic syndromes. Since poly (ADP-ribose) polymerase (PARP) inhibitors have been recently shown to selectively target cells with defects in double-strand DNA repair, the aim of this study was to explore the possibility of exploiting defects in DNA repair in leukemic cells using PARP inhibitors.
  
  
  METHODS
  Leukemic cell lines were exposed to various PARP inhibitors alone and in combination with non-cytotoxic concentrations of DNA methyltransferase inhibitor, 5' aza-2'-deoxycytidine and/or the histone deacetylase inhibitor, MS275, to test for potentiation of apoptosis with these agents.
  
  
  RESULTS
  PARP inhibitors, KU-0058948 and PJ34, induced cell cycle arrest and apoptosis of primary myeloid leukemic cells and myeloid leukemic cell lines in vitro. Immunofluorescence analysis also revealed that PARP inhibitor sensitivity in these leukemic cells was due to a defect in homologous recombination DNA repair. Addition of 5' aza-2'-deoxycytidine failed to increase the cytotoxicity of PARP inhibitors. In contrast, MS275 potentiated the cytotoxic effect of KU-0058948 and PJ34 in all PARP inhibitor-sensitive leukemic cells. Immunofluorescence analysis supported the idea that histone deacetylase inhibitors potentiate cytotoxicity by inhibiting DNA repair processes. Conclusions On the basis of the data presented here, we suggest that PARP inhibitors can potentially exploit defects in double-strand DNA break repair in leukemic cells, paving the way for testing the therapeutic potential of these agents in myelodysplastic syndromes and acute myeloid leukemia.
authors.affiliation: Department of Haematological, Medicine, King's College, London, The Rayne Institute, 123 Coldharbour Lane, London, UK.
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Gaymes
authors.forename: Sydney
authors.initials: S
authors.lastname: Shall
authors.forename: Lee J
authors.initials: LJ
authors.lastname: MacPherson
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Twine
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Lea
authors.forename: Farzin
authors.initials: F
authors.lastname: Farzaneh
authors.forename: Ghulam J
authors.initials: GJ
authors.lastname: Mufti
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects*; D000077209:Decitabine; D004357:Drug Synergism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005464:Fluorobenzenes / Q000494:pharmacology; D018922:HL-60 Cells; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007150:Immunohistochemistry; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010616:Phenanthrenes / Q000494:pharmacology; D010793:Phthalazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D020298:U937 Cells
chemical_list: D001549:Benzamides; D002087:Butyrates; D005464:Fluorobenzenes; D006877:Hydroxamic Acids; C506932:KU0058948; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011725:Pyridines; C118739:entinostat; C012589:trichostatin A; D000077209:Decitabine; D015254:DNA Modification Methylases; D051548:Histone Acetyltransferases; D011065:Poly(ADP-ribose) Polymerases; D001374:Azacitidine