Inhibitors of poly ADP-ribose polymerase (PARP) induce apoptosis of myeloid leukemic cells

Potential for therapy of myeloid leukemia and myelodysplastic syndromes

Terry J. Gaymes, Sydney Shall, Lee J. MacPherson, Natalie A. Twine, Nicholas C. Lea, Farzin Farzaneh, Ghulam J. Mufti

Research output: Contribution to journalArticle

62 Citations (Scopus)

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. Design and 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.

Original languageEnglish
Pages (from-to)638-646
Number of pages9
JournalHaematologica
Volume94
Issue number5
DOIs
Publication statusPublished - May 2009
Externally publishedYes

Keywords

  • Apoptosis
  • DNA repair
  • Histone deacetylation inhibition
  • PARP

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