Poly (ADP-ribose) polymerase inhibitor increases apoptosis and reduces necrosis induced by a DNA minor groove binding methyl sulfonate ester

The poly(ADP-ribose) polymerase (PARP) is involved in cell recovery from DN A damage, such as methylation of N3-adenine, that activates the base excisi on repair process. In the present study we demonstrated that MeOSO2(CH2)(2) -lexitropsin (Me-Lex), a methylating agent that almost exclusively produces N3-methyladenine, induced different modalities of cell death in human leuk emic cell lines, depending on the presence of PARP inhibitor. Growth inhibi tion, provoked by the combination of Me-Lex and PARP inhibitor, was associa ted with a marked down-regulation of c-myc, increased generation of single strand breaks and apoptosis, When used as single agent, at concentrations t hat saturated cell repair ability, Me-Lex induced mainly cell death by necr osis, Surprisingly, addition of a PARP inhibitor enhanced apoptosis and red uced the early appearance of necrosis, Telomerase activity was completely s uppressed in cells exposed to Me-Lex alone, by 24 h after treatment, wherea s it did not change when Me-Lex was combined with PARP inhibitor. Thereafte r, inhibition of telomerase was observed with both treatments. The results suggest new insights on different modalities of cell death induced by high levels of N3-methyladenine per se, or by the methylated base in the presenc e of PARP inhibitor.