N3-methyladenine induces early poly(ADP-ribosylation), reduction of nuclear factor-kappa B DNA binding ability, and nuclear up-regulation of telomerase activity.
Methylation of N3-adenine represents a novel pharmacological strategy for the treatment of resistant tumors. However, little is known about the biochemical pathways involved in cell death induced by N3-methyladenine. In the present study, we show that MeOSO(2) (CH(2))(2)-lexitropsin (Me-Lex), a compound generating almost exclusively N3-methyladenine (>99%), provoked a burst of poly(ADP-ribosylation) and loss of mitochondrial membrane potential in leukemia cells. These events were followed by a marked decrease in nuclear poly(ADP-ribose) polymerase-1 (PARP-1) expression and nuclear factor-kappaB (NF-kappaB) activity. Moreover, DNA damage generated by N3-methyladenine induced a marked decrease in telomerase in the cytosol that was accompanied by a transient up-regulation of activity in the nucleus, as a consequence of nuclear translocation of telomerase in response to genotoxic damage. PARP-1 inhibition blocked ADP-ribose polymer formation, preserved mitochondrial membrane integrity, and counteracted the reduction of NF-kappaB activity, thus preventing the appearance of necrosis. On the other hand, because PARP-1 is a component of the base excision repair (BER), the combination of Me-Lex + PARP-1 inhibitor triggered apoptosis as a result of disruption of BER process. In conclusion, the present study provides new insight into the cellular response to N3-adenine-selective methylating agents that can be exploited for the treatment of tumors unresponsive to classical wide-spectrum methylating agents. Moreover, the results underline the central and paradoxical role of PARP-1 in cell death induced by N3-methyladenine: effector of necrosis and coordinator of methylpurine repair.
Tentori
Lucio
L
Department of Neuroscience, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
Forini
Olindo
O
Fossile
Emanuela
E
Muzi
Alessia
A
Vergati
Matteo
M
Portarena
Ilaria
I
Amici
Carla
C
Gold
Barry
B
Graziani
Grazia
G
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D004247:DNA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011064:Poly Adenosine Diphosphate Ribose / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D019098:Telomerase / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D016328:NF-kappa B; D011064:Poly Adenosine Diphosphate Ribose; C025946:3-methyladenine; D004247:DNA; D019098:Telomerase; D000225:Adenine