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Molecular Determinants Involved in the Increase of Damage‐Induced Apoptosis and Delay of Secondary Necrosis due to Inhibition of Mono(ADP‐Ribosyl)ation
Author(s) -
CERELLA CLAUDIA,
MEARELLI CRISTINA,
AMMENDOLA SERGIO,
DE NICOLA MILENA,
D'ALESSIO MARIA,
MAGRINI ANDREA,
BERGAMASCHI ANTONIO,
GHIBELLI LINA
Publication year - 2006
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1378.005
Subject(s) - apoptosis , poly adp ribose polymerase , programmed cell death , enzyme , signal transduction , in vivo , microbiology and biotechnology , chemistry , necrosis , cell , polymerase , tumor necrosis factor alpha , biochemistry , biology , immunology , genetics
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.