Poly(ADP-ribose) polymerase (PARP) inhibition or PARP-1 gene deletion reduces angiogenesis.
Poly(ADP-ribose) polymerase (PARP)-1 has recently been shown to promote tumour progression. Since angiogenesis is an essential requirement for tumour growth, we examined whether PARP inhibition/deletion might affect endothelial cell functions. To this end, the influence of PARP inhibitors on endothelial cell proliferation, migration, tube formation and angiogenesis in PARP-1 knock-out mice, using an in vivo matrigel plug assay, was investigated. The results indicated that the PARP inhibitor GPI 15427 (IC50 on endothelial PARP: 237 +/- 27 nM), at concentrations devoid of cytotoxic effects (0.5-1 microM), abrogated migration in response to vascular endothelial growth factor or placenta growth factor, hampered formation of tubule-like networks and impaired angiogenesis in vivo. The anti-angiogenic effect of the PARP inhibitor was confirmed in PARP-1 knock-out mice that displayed a defect of angiogenesis induced by growth factors. These results provide evidence for targeting PARP for anti-angiogenesis, adding novel therapeutic implications to the use of PARP inhibitors in cancer treatment.
Tentori
Lucio
L
Department of Neuroscience, University of Rome Tor Vergata, Via Montpellier 1, Rome, Italy.
Lacal
Pedro Miguel
PM
Muzi
Alessia
A
Dorio
Annalisa Susanna
AS
Leonetti
Carlo
C
Scarsella
Marco
M
Ruffini
Federica
F
Xu
Weizheng
W
Min
Wokee
W
Stoppacciaro
Antonella
A
Colarossi
Cristina
C
Wang
Zhao-Qi
ZQ
Zhang
Jie
J
Graziani
Grazia
G
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D002464:Cell Migration Inhibition / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells; D017353:Gene Deletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D009930:Organic Chemicals / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D050257:Tubulin Modulators / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D009930:Organic Chemicals; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D050257:Tubulin Modulators; D042461:Vascular Endothelial Growth Factor A; D011064:Poly Adenosine Diphosphate Ribose; C502278:GPI 15427; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases