Targeting angiogenesis with poly(ADP-ribose) polymerase inhibitors

The process of angiogenesis is mediated by a wide range of factors, including pro-inflammatory cytokines. On the basis of the involvement of inflammation in tumor development and of the dual role of PARP inhibitor as enhancer of chemotherapy or as anti-inflammatory agent we have investigated the ability of PARP inhibitors to affect endothelial functions and vessel formation. To this end the influence of PARP inhibition on endothelial cell proliferation, migration, in vitro tube formation and on in vivo angiogenesis, using a matrigel plug assay, was investigated. For the in vitro studies we used an immortalized human endothelial cell line (HUV-ST), which displays all major endothelial phenotypic markers and is capable of organizing into tubule-like networks in response to appropriate stimuli. The results indicated that the PARP inhibitor GPI 15427, at concentrations devoid of antiproliferative or cytotoxic effects, abrogated migration in response to vascular endothelial growth factor (VEGF) or Placental growth factor (PlGF) and only slightly inhibited endothelial chemotaxis triggered by other stimuli like Epidermal growth factor (EGF) and basic Fibroblast growth factor (bFGF). Moreover, GPI 15427 significantly reduced the ability of HUV-ST cells to form tube and capillary-like structures in a dose-dependent manner. The in vivo angiogenesis studies using subcutaneous implantation of matrigel gel sponges containing angiogenic factors confirmed the anti-angiogenic effects of the PARP inhibitor. Taken together these results provide evidences for a role of PARP on endothelial functions important during the angiogenetic process and for the anti-angiogenic properties of PARP inhibitors, encouraging further studies on the potential mechanisms underlying this effect. Supported by: PRIN 2004 to GG and PRIN 2005 to LT.