Inhibition of angiogenesis by the poly(ADP-ribose) polymerase inhibitor PJ-34

Anastasia Pyriochou, Gabor Olah, Edwin A. Deitch, Csaba Szabó, Andreas Papapetropoulos

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Angiogenesis-related treatments have a broad spectrum of potential applications ranging from cancer to macular degeneration, to wound healing. Thus, the identification of pharmacological agents that modulate new blood vessel formation has attracted much attention. In the present study, we investigated the effects of the poly(ADP-ribose) polymerase (PARP) inhibitor PJ-34 [N-(6-Oxo-5,6-dihydro-phenanthridin -2-yl)-N,N-dimethylacetamide] on angiogenesis. Treatment of chicken chorioallantoic membranes (CAM) with PJ-34 reduced vascular length in these tissues; paradoxically, lower doses of PJ-34 (0.03 or 0.3 nmol/ cm2) were more effective in inhibiting neovascularisation than higher doses (3 or 30 nmol/cm2). In vitro, incubation of endothelial cells (EC) with PJ-34 (300 nM to 10 μM) inhibited their proliferation in a concentration-dependent manner with maximal inhibition of 22.3% being observed at 10 μM. Capillary morphogenesis of EC grown on Matrigel was also negatively affected by PJ-34. In addition, PJ-34 abolished the migratory response to the prototype angiogenic factor vascular endothelial growth factor (VEGF) and reduced VEGF-stimulated activation of members of the mitogen activated protein kinase family (ERK1/2, p38), as well as Akt. PJ-34 also inhibited VEGF-induced NO release and cGMP accumulation. In conclusion, we provide evidence that PARP inhibition blocks angiogenesis-related EC properties by interfering with multiple signalling pathways leading to the inhibition of new blood vessel formation.

Original languageEnglish (US)
Pages (from-to)113-118
Number of pages6
JournalInternational journal of molecular medicine
Volume22
Issue number1
StatePublished - Jul 1 2008

Keywords

  • Angiogenesis
  • Poly(ADP-ribose)
  • Polymerase inhibitor

ASJC Scopus subject areas

  • Genetics

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