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Poly(ADP-ribose) polymerase (PARP)-1 has recently been shown to promote tumor progression through its transcriptional regulatory activity. Since angiogenesis is an essential requirement for tumor growth, we investigated whether PARP inhibition might affect endothelial cell functions and vessel formation.

To this end, the effect of PARP inhibitors on endothelial cell proliferation, migration, tube formation and on in vivo angiogenesis, using a matrigel plug assay, was assessed. For the in vitro studies we used an immortalized human endothelial cell line (HUV-ST), which displays all major endothelial phenotypes and forms tubule-like networks in response to stimuli by growth factors.

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 uM), abrogated migration in response to vascular endothelail growth factor (VEGF) or placenta growth factor (PlGF) and hampered the ability of HUV-ST cells to form tubule-like networks. Moreover, the PARP inhibitor impaired in vivo angiogenesis as measured by the matrigel plug assay. The anti-angiogenic effect of the PARP inhibitor was confirmed in mice with PARP-1 gene deletion (PARP-1 KO), which displayed a defect of in vivo angiogenesis induced by growth factors.

These results from studies using either PARP inhibitors of PARP-1 KO mice provide evidence for targeting PARP for anti-angiogenesis. The discovery adds novel therapeutic implications to the use of PARP inhibitors for cancer treatment.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA