Inhibition of angiogenesis by the poly(ADP-ribose) polymerase inhibitor PJ-34

Abstract

Abstract. 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/cm 2 ) were more effective in inhibiting neovascularisation than higher doses (3 or 30 nmol/cm 2 ). In vitro, incubation of endothelial cells (EC) with PJ-34 (300 nM to 10 μM) inhibited their proliferation in a concentration-dependent manner with maximal inhibition of 22.3% being observed at 10 μM. 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 VEGFstimulated 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.

Pharmacological inhibition of poly(ADP-ribose) polymerase activity down-regulates the expression of syndecan-4 and Id-1 in endothelial cells

“…The observed anti-angiogenic effect of GPI 15427 is associated with a decrease of endothelial cell migration in response to angiogenic factors, such as the vascular endothelial growth factor (VEGF) or the placenta growth factor, and cannot be directly related to increased DNA damage, since it is observed at drug concentrations that do not affect the viability and the proliferative potential of endothelial cells. Similar anti-angiogenic effects were obtained also with other PARP inhibitors (11)(12)(13). Notably, abrogation of PARP-1 expression by stable gene silencing reduced the aggressiveness of melanoma and this effect was associated with a decreased vasculature formation within the tumour (14).…”

The poly(ADP-ribose) polymerase-1 inhibitor 3-aminobenzamide suppresses cell growth and migration, enhancing suppressive effects of cisplatin in osteosarcoma cells

“…In certain types of tumors including lung cancer, colon carcinoma and cervical cancer, pArp-1 inhibition was shown to be an effective means of enhancing tumor sensitivity to radiation and chemotherapy (16)(17)(18)(19), also pArp inhibitor could be used as single agents to selectively kill cancers defective in DnA repair, specifically cancers with mutations in the breast cancerassociated genes (BrcA1 and BrcA2) (20,21). Additionally, a number of reports have shown a relationship between pArp and angiogenesis, at least five pArp inhibitors have been efficiently used in vitro (22)(23)(24) to inhibit vascular endothelial growth factor (VegF)-induced proliferation, migration, and tube formation in human umbilical vein endothelial cells (HUVecs). However, whether or not pArp-1 inhibitor is able to suppress tumor cell growth and migration and whether it improves chemotherapeutic effects in human osteosarcoma have rarely been studied.…”

Effect of silencing PARG in human colon carcinoma LoVo cells on the ability of HUVEC migration and proliferation

“…Moreover, a PARP inhibitor was found to inhibit p38 expression and cause the phosphorylation of retinal neurons in mice model of chronic hypoperfusion and chorionic cells in chicks. 8,9 It has also been reported that inhibiting PARP could adjust p38 10 and that ERK phosphorylation of the MAPK pathway, could then downregulate nuclear factor (NF)-kB transcriptional 11 activity and consequently decrease the expressions of NF-kB-dependent genes such as intercellular cell adhesion molecule (ICAM-1), which is important during inflammatory processes. As, our previous results also demonstrated that inhibiting PARP could inhibit NF-kB activity in mice colon cancer CT26 cells; 12 vascular endothelial growth factor (VEGF), b-FGF (basic fibroblast growth factor), ICAM-1 and matrix metalloproteinases (MMP)-9 being well known NF-kB-dependent angiogenic-related factors, reflecting the relative migratory and proliferative ability of tumors were assessed in our experimental trial.…”