Specific inhibitors of poly(ADP-ribose) synthetase and mono(ADP-ribosyl)transferase.

Banasik, Marek; Komura, Hajime; Shimoyama, Makoto; Ueda, Kunihiro

doi:10.1016/s0021-9258(18)45983-2

Cited by 416 publications

(67 citation statements)

References 49 publications

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“…To induce a systemic inflammatory response, we applied endotoxin (LPS 0111:B4 from Escherichia coli; Sigma) to the animals of the LPS group [100 g as bolus and 20 g/(h ⅐ kg ⅐ body wt) per infusionem]. The rabbits of the 3-AB group received the PARS inhibitor 3-AB (Sigma) [10 mg as bolus and 5 mg/(h ⅐ kg ⅐ body wt) per infusionem] (1,31,36,39). The LPS ϩ 3-AB group consisted of rabbits treated with the combination of LPS and 3-AB.…”

Section: Animalsmentioning

confidence: 99%

Role of poly(ADP-ribose) synthetase in pulmonary leukocyte recruitment

Kiefmann

Heckel²,

Dörger³

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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During systemic inflammation, recruitment and activation of leukocytes in the pulmonary microcirculation may result in a potentially life-threatening acute lung injury. We elucidated the role of the poly(ADP-ribose) synthetase (PARS), a nucleotide-polymerizing enzyme, in the regulation of leukocyte recruitment within the lung with regard to the localization in the pulmonary microcirculation and in correlation to hemodynamics in the respective vascular segments and expression of intercellular adhesion molecule 1 during endotoxemia. Inhibition of PARS by 3-aminobenzamide reduced the endotoxin-induced leukocyte recruitment within pulmonary arterioles, capillaries, and venules in rabbits as quantified by in vivo fluorescence microscopy. Microhemodynamics and thus shear rates in all pulmonary microvascular segments remained constant. Simultaneously, inhibition of PARS with 3-aminobenzamide suppressed the endotoxin-induced adhesion molecules expression as demonstrated for intercellular adhesion molecule 1 by immunohistochemistry and Western blot analysis. We confirmed this result with the use of PARS knockout mice. The inhibitory effect of 3-aminobenzamide on leukocyte recruitment was associated with a reduction of pulmonary capillary leakage and edema formation. We first provide evidence that PARS activation mediates the leukocyte sequestration in pulmonary microvessels through upregulation of adhesion molecules. As reactive oxygen species released from leukocyte are supposed to cause an upregulation of adhesion molecules we conclude that PARS inhibition contributes to termination of this vicious cycle and inhibits the inflammatory process.

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Section: Animalsmentioning

confidence: 99%

Role of poly(ADP-ribose) synthetase in pulmonary leukocyte recruitment

Kiefmann

Heckel²,

Dörger³

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Several studies have described mechanisms of actions of PARP inhibitors other than via DNA repair pathways, including metastasis, tumor angiogenesis and neuronal death [18,21,22]. Some available PARP1 inhibitors, many of which contain a nicotinamide/ benzamide pharmacophore group, competitively inhibit the binding of PARP1 to NAD + [23,24].…”

Section: Introductionmentioning

confidence: 99%

Nutlin-3a suppresses poly (ADP-ribose) polymerase 1 by mechanisms different from conventional PARP1 suppressors in a human breast cancer cell line

et al. 2020

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Poly (ADP-ribose) polymerase 1 (PARP1) plays important roles in single strand DNA repair. PARP1 inhibitors enhance the effects of DNA damaging drugs in homologous recombination-deficient tumors including tumors with breast cancer susceptibility gene (BRCA1) mutation. Nutlin-3a, an analog of cis-imidazoline, inhibits degradation of murine double minute 2 (MDM2) and stabilizes p53. We previously reported that nutlin-3a induces PARP1 degradation in p53-dependent manner in mouse fibroblasts, suggesting nutlin-3a may be a PARP1 suppressor. Here, we investigated the effects of nutlin-3a on PARP1 in MCF-7, a human breast cancer cell line. Consistent with our previous results, nutlin-3a reduced PARP1 levels in doseand time-dependent manners in MCF-7 cells, but this reduction was suppressed in p53 knockdown cells. RITA, a p53 stabilizer that binds to p53 itself, failed to reduce PARP1 protein levels. Moreover, transient MDM2 knockdown repressed nutlin-3amediated PARP1 reduction. The MG132 proteasome inhibitor, and knockdown of checkpoint with forkhead and ring finger domains (CHFR) and ring finger protein 146 (RNF146), E3 ubiquitin ligases targeting PARP1, suppressed nutlin-3a-induced PARP1 reduction. Short-term nutlin-3a treatment elevated the levels of PARylated PARP1, suggesting nutlin-3a promoted PARylation of PARP1, thereby inducing its proteasomal degradation. Furthermore, nutlin-3a-induced PARP1 degradation enhanced DNA-damaging effects of cisplatin in BRCA1 knockdown cells. Our study revealed that nutlin-3a is a PARP1 suppressor that induces PARP1 proteasomal degradation by binding to MDM2 and promoting autoPARylation of PARP1. Further analysis of the mechanisms in nutlin-3a-induced PARP1 degradation may lead to the development of novel PARP1 suppressors applicable for cancers with BRCA1 mutation.

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“…Cytotoxicity studies were carried out to probe whether 1 ‐mediated osteosarcoma cell death was related to PARP‐1 activation. Specifically, the potency of 1 towards U2OS cells was measured in the presence of veliparib (ABT‐888, 10 μM) and 4‐amino‐1,8‐naphthalimide (ANA, 10 μM), both well‐known PARP‐1 inhibitors. The change in potency of 1 in the presence of ABT‐888 and ANA was not statistically significant ( p >0.05; Figures S11 and S12).…”

Section: Resultsmentioning

confidence: 99%

The Bulk Osteosarcoma and Osteosarcoma Stem Cell Activity of a Necroptosis‐Inducing Nickel(II)–Phenanthroline Complex

Eskandari

Flamme²,

Xiao

et al. 2020

ChemBioChem

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We report the anti-osteosarcoma and anti-osteosarcoma stem cell (OSC) properties of a nickel(II) complex, 1. Complex 1 displays similar potency towards bulk osteosarcoma cells and OSCs, in the micromolar range. Notably, 1 displays similar or better OSC potency than the clinically approved platinum(II) anticancer drugs cisplatin and carboplatin in two-and threedimensional osteosarcoma cell cultures. Mechanistic studies revealed that 1 induces osteosarcoma cell death by necroptosis, an ordered form of necrosis. The nickel(II) complex, 1 triggers necrosome-dependent mitrochondrial membrane depolarisa-tion and propidium iodide uptake. Interestingly, 1 does not evoke necroptosis by elevating intracellular reactive oxygen species (ROS) or hyperactivation of poly ADP ribose polymerase (PARP-1). ROS elevation and PARP-1 activity are traits that have been observed for established necroptosis inducers such as shikonin, TRAIL and glutamate. Thus the necroptosis pathway evoked by 1 is distinct. To the best of our knowledge, this is the first report into the anti-osteosarcoma and anti-OSC properties of a nickel complex.

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Specific inhibitors of poly(ADP-ribose) synthetase and mono(ADP-ribosyl)transferase.

Cited by 416 publications

References 49 publications

Role of poly(ADP-ribose) synthetase in pulmonary leukocyte recruitment

Role of poly(ADP-ribose) synthetase in pulmonary leukocyte recruitment

Nutlin-3a suppresses poly (ADP-ribose) polymerase 1 by mechanisms different from conventional PARP1 suppressors in a human breast cancer cell line

The Bulk Osteosarcoma and Osteosarcoma Stem Cell Activity of a Necroptosis‐Inducing Nickel(II)–Phenanthroline Complex

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