gpi-15427 and Neoplasms

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.

Topics: Angiogenesis Inhibitors; Animals; Cell Migration Inhibition; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Endothelial Cells; Gene Deletion; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasms; Neovascularization, Pathologic; Organic Chemicals; Poly (ADP-Ribose) Polymerase-1; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Tubulin Modulators; Vascular Endothelial Growth Factor A