Evaluation of poly (ADP-ribose) polymerase inhibitor ABT-888 combined with radiotherapy and temozolomide in glioblastoma

Radiat Oncol. 2013 Mar 19;8:65. doi: 10.1186/1748-717X-8-65.

Abstract

Background: The cytotoxicity of radiotherapy and chemotherapy can be enhanced by modulating DNA repair. PARP is a family of enzymes required for an efficient base-excision repair of DNA single-strand breaks and inhibition of PARP can prevent the repair of these lesions. The current study investigates the trimodal combination of ABT-888, a potent inhibitor of PARP1-2, ionizing radiation and temozolomide(TMZ)-based chemotherapy in glioblastoma (GBM) cells.

Methods: Four human GBM cell lines were treated for 5 h with 5 μM ABT-888 before being exposed to X-rays concurrently with TMZ at doses of 5 or 10 μM for 2 h. ABT-888's PARP inhibition was measured using immunodetection of poly(ADP-ribose) (pADPr). Cell survival and the different cell death pathways were examined via clonogenic assay and morphological characterization of the cell and cell nucleus.

Results: Combining ABT-888 with radiation yielded enhanced cell killing in all four cell lines, as demonstrated by a sensitizer enhancement ratio at 50% survival (SER50) ranging between 1.12 and 1.37. Radio- and chemo-sensitization was further enhanced when ABT-888 was combined with both X-rays and TMZ in the O6-methylguanine-DNA-methyltransferase (MGMT)-methylated cell lines with a SER50 up to 1.44. This effect was also measured in one of the MGMT-unmethylated cell lines with a SER50 value of 1.30. Apoptosis induction by ABT-888, TMZ and X-rays was also considered and the effect of ABT-888 on the number of apoptotic cells was noticeable at later time points. In addition, this work showed that ABT-888 mediated sensitization is replication dependent, thus demonstrating that this effect might be more pronounced in tumour cells in which endogenous replication lesions are present in a larger proportion than in normal cells.

Conclusions: This study suggests that ABT-888 has the clinical potential to enhance the current standard treatment for GBM, in combination with conventional chemo-radiotherapy. Interestingly, our results suggest that the use of PARP inhibitors might be clinically significant in those patients whose tumour is MGMT-unmethylated and currently derive less benefit from TMZ.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / administration & dosage*
  • Benzimidazoles / administration & dosage*
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • Chemoradiotherapy / methods*
  • Dacarbazine / administration & dosage
  • Dacarbazine / analogs & derivatives
  • Enzyme Inhibitors / administration & dosage
  • Fluorescent Antibody Technique
  • Glioblastoma*
  • Humans
  • Poly(ADP-ribose) Polymerases / drug effects
  • Poly(ADP-ribose) Polymerases / metabolism
  • Temozolomide

Substances

  • Antineoplastic Agents
  • Benzimidazoles
  • Enzyme Inhibitors
  • veliparib
  • Dacarbazine
  • Poly(ADP-ribose) Polymerases
  • Temozolomide