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 DNA damage, such as methylation of N3-adenine, that activates the base excision repair process. In the present study we demonstrated that MeOSO(2)(CH(2))(2)-lexitropsin (Me-Lex), a methylating agent that almost exclusively produces N3-methyladenine, induced different modalities of cell death in human leukemic cell lines, depending on the presence of PARP inhibitor. Growth inhibition, provoked by the combination of Me-Lex and PARP inhibitor, was associated with a marked down-regulation of c-myc, increased generation of single strand breaks and apoptosis. When used as single agent, at concentrations that saturated cell repair ability, Me-Lex induced mainly cell death by necrosis. Surprisingly, addition of a PARP inhibitor enhanced apoptosis and reduced the early appearance of necrosis. Telomerase activity was completely suppressed in cells exposed to Me-Lex alone, by 24 h after treatment, whereas it did not change when Me-Lex was combined with PARP inhibitor. Thereafter, 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 presence of PARP inhibitor.
Tentori
L
L
Pharmacology and Medical Oncology Section, Department of Neuroscience, University of Rome Tor Vergata, Via di Tor Vergata 135, 00133 Rome, Italy.
Balduzzi
A
A
Portarena
I
I
Levati
L
L
Vernole
P
P
Gold
B
B
Bonmassar
E
E
Graziani
G
G
D000477:Alkylating Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects* / Q000502:physiology; D045647:DNA Glycosylases; D019175:DNA Methylation / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects* / Q000502:physiology; D004277:DNA, Single-Stranded / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D019169:Jurkat Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009699:N-Glycosyl Hydrolases / Q000378:metabolism; D009336:Necrosis; D009429:Netropsin / Q000031:analogs & derivatives / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D019098:Telomerase / Q000187:drug effects / Q000378:metabolism
D000477:Alkylating Agents; D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; C110963:methyl lexitropsin; D009429:Netropsin; D011065:Poly(ADP-ribose) Polymerases; D019098:Telomerase; C021565:3-methyladenine-DNA glycosylase; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases