Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells

Cell Death Differ. 2014 Feb;21(2):258-69. doi: 10.1038/cdd.2013.136. Epub 2013 Oct 11.


Glioblastoma-initiating cells (GICs) are self-renewing tumorigenic sub-populations, contributing to therapeutic resistance via decreased sensitivity to ionizing radiation (IR). GIC survival following IR is attributed to an augmented response to genotoxic stress. We now report that GICs are primed to handle additional stress due to basal activation of single-strand break repair (SSBR), the main DNA damage response pathway activated by reactive oxygen species (ROS), compared with non-GICs. ROS levels were higher in GICs and likely contributed to the oxidative base damage and single-strand DNA breaks found elevated in GICs. To tolerate constitutive DNA damage, GICs exhibited a reliance on the key SSBR mediator, poly-ADP-ribose polymerase (PARP), with decreased viability seen upon small molecule inhibition to PARP. PARP inhibition (PARPi) sensitized GICs to radiation and inhibited growth, self-renewal, and DNA damage repair. In vivo treatment with PARPi and radiotherapy attenuated radiation-induced enrichment of GICs and inhibited the central cancer stem cell phenotype of tumor initiation. These results indicate that elevated PARP activation within GICs permits exploitation of this dependence, potently augmenting therapeutic efficacy of IR against GICs. In addition, our results support further development of clinical trials with PARPi and radiation in glioblastoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • DNA Damage
  • DNA Repair
  • Dose-Response Relationship, Drug
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology*
  • Glioblastoma / therapy
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology*
  • Phenotype
  • Phthalazines / pharmacology
  • Piperazines / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Reactive Oxygen Species / metabolism
  • Structure-Activity Relationship


  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Reactive Oxygen Species
  • Poly(ADP-ribose) Polymerases
  • olaparib