title: Molecular determinants involved in the increase of damage-induced apoptosis and delay of secondary necrosis due to inhibition of mono(ADP-ribosyl)ation.
abstract: ADP-ribosylations are reversible posttranslational modifications that regulate the activity of target proteins, catalyzed by two different classes of enzymes, namely poly(ADP-ribosyl)polymerases (PARPs) and mono(ADP-ribosyl)transferases (ADPRTs). It is now emerging that ADP-ribosylation reactions control signal transduction pathways, mostly as a response to cell damage, aimed at both cell repair and apoptosis. Inhibition of ADPRTs, but not PARPs, increases the extent of apoptosis induced by cytocidal treatments, at the same time delaying secondary necrosis, the process leading to plasma membrane collapse in apoptotic cells, and responsible for apoptosis-related inflammation in vivo. Thus, ADPRT inhibitors may be ideal as adjuvants to cytocidal therapies; to this purpose, we investigated the molecular determinant(s) for such effects by probing a set of molecules with similar structures. We found that the apoptosis-modulating effects were mimicked by those compounds possessing an amidic group in the same position as two of the most popular ADPRT inhibitors, namely, 3-aminobenzamide and nicotinamide. This study may provide useful suggestions in designing molecules with therapeutic potential to be used as adjuvant in cytocidal therapies.
authors: Dipartimento di Biologia, Università di Roma Tor Vergata, via Ricerca Scientifica 1, 00133 Roma, Italy. cerella@uniroma2.it
authors: Claudia
authors: C
authors: Cerella
authors: Cristina
authors: C
authors: Mearelli
authors: Sergio
authors: S
authors: Ammendola
authors: Milena
authors: M
authors: De Nicola
authors: Maria
authors: M
authors: D'Alessio
authors: Andrea
authors: A
authors: Magrini
authors: Antonio
authors: A
authors: Bergamaschi
authors: Lina
authors: L
authors: Ghibelli
mesh_terms: D036002:ADP Ribose Transferases / Q000378:metabolism; D000246:Adenosine Diphosphate Ribose / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017209:Apoptosis; D006801:Humans; D009336:Necrosis; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D020298:U937 Cells
chemical_list: D000246:Adenosine Diphosphate Ribose; D036002:ADP Ribose Transferases; D011065:Poly(ADP-ribose) Polymerases