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.

Mono-galloyl glucose derivatives are potent poly(ADP-ribose) glycohydrolase (PARG) inhibitors and partially reduce PARP-1-dependent cell death / L. Formentini; P. Arapistas; M. Pittelli; M. Jacomelli; V. Pitozzi; S. Menichetti; A. Romani; L. Giovannelli; F. Moroni; A. Chiarugi. - In: BRITISH JOURNAL OF PHARMACOLOGY. - ISSN 0007-1188. - ELETTRONICO. - 155:(2008), pp. 1235-1249. [10.1038/bjp.2008.370]

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

FORMENTINI, LAURA;PITTELLI, MARIA;PITOZZI, VANESSA;MENICHETTI, STEFANO;ROMANI, ANNALISA;GIOVANNELLI, LISA;MORONI, FLAVIO;CHIARUGI, ALBERTO
2008

Abstract

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.
2008
155
1235
1249
L. Formentini; P. Arapistas; M. Pittelli; M. Jacomelli; V. Pitozzi; S. Menichetti; A. Romani; L. Giovannelli; F. Moroni; A. Chiarugi
File in questo prodotto:
File Dimensione Formato  
2008 BJP.pdf

Accesso chiuso

Tipologia: Altro
Licenza: Tutti i diritti riservati
Dimensione 463.36 kB
Formato Adobe PDF
463.36 kB Adobe PDF   Richiedi una copia

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/395112
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 39
  • ???jsp.display-item.citation.isi??? 32
social impact