Poly(ADP-ribose) polymerase (PARP) inhibition or PARP-1 gene deletion reduces angiogenesis

Tentori, Lucio; Lacal, Pedro Miguel; Muzi, Alessia; Dorio, Annalisa Susanna; Leonetti, Carlo; Scarsella, Marco; Ruffini, Federica; Xu, Weizheng; Min, Wokee; Stoppacciaro, Antonella; Colarossi, Cristina; Wang, Zhao Qi; Zhang, Jie; Graziani, Grazia

doi:10.1016/j.ejca.2007.07.010

Cited by 122 publications

(88 citation statements)

References 28 publications

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“…Lower PJ-34 might preferentially inhibit pathways leading to the expression of angiogenic factors or induce the production of endogenous angiogenesis inhibitors, while as PJ-34 concentrations increase, inhibitory pathways are switched off. Our findings that PARP inhibition reduces neovascularization in the CAM are in line with the observation that PARP-1 deletion or administration of a PARP inhibitor (GPI-15427) attenuates VEGF-driven angiogenesis in the Matrigel plug assay in mice (19).…”

Section: Discussionsupporting

confidence: 77%

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

Pyriochou

Oláh²,

Deitch

et al. 2008

Int J Mol Med

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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.

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Section: Discussionsupporting

confidence: 77%

“…Under the conditions used, PARP inhibition abolished VEGF-driven migration. As earlier studies have indicated that PARP inhibition attenuates VEGF-and fibroblast growth factor-, but not epidermal growth factorinduced migration (13,19), PARP inhibition might selectively affect certain angiogenic pathways.…”

Section: Discussionmentioning

confidence: 99%

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

Pyriochou

Oláh²,

Deitch

et al. 2008

Int J Mol Med

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“…Further, tumor regression resulting from combinatorial treatment indicates widespread tumor efficacy owing to a direct effect on nonGICs and/or the reported antiangiogenic effect of PARPi. 46,47 Our data, however, do indicate that PARPi before irradiation compromises the ability of GICs to respond to DNA damage, driving the cells to undergo apoptosis.…”

Section: Discussionmentioning

confidence: 58%

Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells

et al. 2013

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Glioblastoma-initiating cells (GICs) are self-renewing tumorigenic sub-populations, contributing to therapeutic resistance via decreased sensitivity to ionizing radiation (IR). GIC survival following IR is attributed to an augmented response to genotoxic stress. We now report that GICs are primed to handle additional stress due to basal activation of single-strand break repair (SSBR), the main DNA damage response pathway activated by reactive oxygen species (ROS), compared with non-GICs. ROS levels were higher in GICs and likely contributed to the oxidative base damage and single-strand DNA breaks found elevated in GICs. To tolerate constitutive DNA damage, GICs exhibited a reliance on the key SSBR mediator, poly-ADP-ribose polymerase (PARP), with decreased viability seen upon small molecule inhibition to PARP. PARP inhibition (PARPi) sensitized GICs to radiation and inhibited growth, self-renewal, and DNA damage repair. In vivo treatment with PARPi and radiotherapy attenuated radiation-induced enrichment of GICs and inhibited the central cancer stem cell phenotype of tumor initiation. These results indicate that elevated PARP activation within GICs permits exploitation of this dependence, potently augmenting therapeutic efficacy of IR against GICs. In addition, our results support further development of clinical trials with PARPi and radiation in glioblastoma.

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“…These processes are important in the survival of the cells after extensive DNA damage but in normal cells the complete absence of PARP-1 protein or the inhibition of PARP-1 catalytic activity produces no significant growth defect [33]. This is supported by the observation that PARP-1 defective mice survive and have no obvious growth defect [34].…”

Section: Parp Inhibition Decreases the Paclitaxel Induced Caspase-3 Amentioning

confidence: 96%

PARP-1 inhibition-induced activation of PI-3-kinase-Akt pathway promotes resistance to taxol

Szántó

Hellebrand

Bognár

et al. 2009

Biochemical Pharmacology

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Running Title: PARP inhibition promotes Taxol resistance via Akt activationThe nonstandard abbreviations used are: PARP, Poly (ADP-ribose) polymerase; PAR, poly (ADP-ribose); PI-3K, phosphatidylinositol-3-kinase; Akt/PKB, protein kinase B; MTT + , 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl-tetrazolium bromide. When activation of the PI-3-kinase-Akt pathway was prevented by LY-294002 or Akt Inhibitor IV, the cytoprotective effect of PARP inhibition was significantly diminished showing that the activation of PI-3-kinase-Akt cascade had significantly contributed to the cytostatic resistance.Our study demonstrates that drug-induced drug resistance can be responsible for the reduced efficacy of antitumor treatment. Although inhibition of PARP-1 can promote cell death in tumor cells by the inhibition of DNA repair, PARP-inhibition promoted activation of the PI-3-kinaseAkt pathway can counteract this facilitating effect, and can cause cytostatic resistance. We suggest augmenting PARP inhibition by the inhibition of the PI-3-kinase-Akt pathway for antitumor therapy.

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Poly(ADP-ribose) polymerase (PARP) inhibition or PARP-1 gene deletion reduces angiogenesis

Cited by 122 publications

References 28 publications

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

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

Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells

PARP-1 inhibition-induced activation of PI-3-kinase-Akt pathway promotes resistance to taxol

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