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Inhibitors of poly ADP-ribose polymerase (PARP) induce apoptosis of myeloid leukemic cells: potential for therapy of myeloid leukemia and myelodysplastic syndromes
- Source :
- Haematologica
- Publication Year :
- 2009
- Publisher :
- Ferrata Storti Foundation, 2009.
-
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.
- Subjects :
- DNA Repair
DNA repair
Cell Survival
Pyridines
Poly ADP ribose polymerase
Decitabine
DNA Methyltransferase Inhibitor
Fluorescent Antibody Technique
Apoptosis
HL-60 Cells
Biology
Poly(ADP-ribose) Polymerase Inhibitors
Hydroxamic Acids
Poly (ADP-Ribose) Polymerase Inhibitor
Cell Line
Cell Line, Tumor
hemic and lymphatic diseases
medicine
Humans
DNA Modification Methylases
Histone Acetyltransferases
Cell Cycle
Myeloid leukemia
Drug Synergism
U937 Cells
Hematology
Phenanthrenes
medicine.disease
Flow Cytometry
Immunohistochemistry
Fluorobenzenes
Butyrates
Leukemia, Myeloid
Myelodysplastic Syndromes
PARP inhibitor
Benzamides
Cancer research
Azacitidine
Phthalazines
Original Article
Errata Corrige
Poly(ADP-ribose) Polymerases
K562 Cells
medicine.drug
Chronic myelogenous leukemia
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Haematologica
- Accession number :
- edsair.doi.dedup.....a39dd695dc12617c6e923dae581078f0