Mono‐galloyl glucose derivatives are potent poly(ADP‐ribose) glycohydrolase (PARG) inhibitors and partially reduce PARP‐1‐dependent cell death

Mono‐galloyl glucose derivatives are potent poly(ADP‐ribose) glycohydrolase (PARG) inhibitors and partially reduce PARP‐1‐dependent cell death

Background and purpose: Maintenance of poly(ADP‐ribose) (PAR) polymers at homoeostatic levels by PAR glycohydrolase (PARG) is central in cell functioning and survival. Yet the pharmacological relevance of PARG inhibitors is still debated. Gallotannin, a complex mixture of hydrolysable tannins from o...

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Bibliographic Details
Published in:British journal of pharmacology Vol. 155; no. 8; pp. 1235 - 1249
Main Authors: Formentini, L, Arapistas, P, Pittelli, M, Jacomelli, M, Pitozzi, V, Menichetti, S, Romani, A, Giovannelli, L, Moroni, F, Chiarugi, A
Format: Journal Article
Language:English
Published: Oxford, UK Blackwell Publishing Ltd 01-12-2008
Nature Publishing Group
Subjects:
Biological and medical sciences
cell death
Cell Death - drug effects
Chromatography, High Pressure Liquid
Enzyme Inhibitors - pharmacology
Glycoside Hydrolases - antagonists & inhibitors
HeLa Cells
Humans
Hydrolyzable Tannins - pharmacology
Magnetic Resonance Spectroscopy
Medical sciences
PARG
PARP
Pharmacology. Drug treatments
Poly(ADP-ribose) Polymerases - metabolism
poly(ADP‐ribose)
Research Papers
Spectrometry, Mass, Electrospray Ionization
Structure-Activity Relationship
tannins
Polyphenol
Tannin
Cell death
PARC
Phenols
Inhibitor
PARP
Glucose
poly(ADP-ribose)
tannins
Gallic acid derivatives
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Summary:Background and purpose: Maintenance of poly(ADP‐ribose) (PAR) polymers at homoeostatic levels by PAR glycohydrolase (PARG) is central in cell functioning and survival. Yet the pharmacological relevance of PARG inhibitors is still debated. Gallotannin, a complex mixture of hydrolysable tannins from oak gall, inhibits PARG but which of its constituents is responsible for the inhibition and whether the pharmacodynamic properties are due to its antioxidant properties, has not yet been established. Experimental approach: A structure–activity relationship study was conducted on different natural and synthetic tannins/galloyl derivatives as potential PARG inhibitors, using a novel in vitro enzymic assay. Cytotoxicity was assayed in cultured HeLa cells. Key results: Mono‐galloyl glucose compounds were potent inhibitors of PARG, with activities similar to that of ADP‐(hydroxymethyl) pyrrolidinediol, the most potent PARG inhibitor yet identified. When tested on HeLa cells exposed to the PAR polymerase (PARP)‐1‐activating compound 1‐methyl‐3‐nitro‐1‐nitrosoguanidine (MNNG), 3‐galloyl glucose weakly inhibited PAR degradation. Conversely, the more lipophilic, 3‐galloyl‐1,2‐O‐isopropylidene glucose, despite being inactive on the pure enzyme, efficiently prolonged the half‐life of the polymers in intact HeLa cells. Also, PARG inhibitors, but not radical scavengers, reduced, in part, cell death caused by MNNG. Conclusions and implications: Taken together, our findings identify mono‐galloyl glucose derivatives as potent PARG inhibitors, and emphasize the active function of this enzyme in cell death. British Journal of Pharmacology (2008) 155, 1235–1249; doi:10.1038/bjp.2008.370; published online 22 September 2008
Bibliography:These two authors contributed equally to this work.
ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:0007-1188
1476-5381
DOI:10.1038/bjp.2008.370