Inhibition of angiogenesis by the poly(ADP-ribose) polymerase inhibitor PJ-34.
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 microM) inhibited their proliferation in a concentration-dependent manner with maximal inhibition of 22.3% being observed at 10 microM. 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.
Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece.
Anastasia
A
Pyriochou
Gabor
G
Olah
Edwin A
EA
Deitch
Csaba
C
Szabó
Andreas
A
Papapetropoulos
D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000196:embryology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D009024:Morphogenesis / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010616:Phenanthrenes / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D006162:Guanylate Cyclase; D006152:Cyclic GMP