N3-methyladenine induces early poly(ADP-ribosylation), reduction of nuclear factor-kappa B DNA binding ability, and nuclear up-regulation of telomerase activity.

Abstract

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.

• Authors: Lucio Tentori, Olindo Forini, Emanuela Fossile, Alessia Muzi, Matteo Vergati, Ilaria Portarena, Carla Amici, Barry Gold, Grazia Graziani
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 67 Issue 2 Pg. 572-81 (Feb 2005) ISSN: 0026-895X [Print] United States
• PMID: 15548765 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• Poly Adenosine Diphosphate Ribose
• 3-methyladenine
• DNA
• Telomerase
• Adenine

Topics

• Adenine (analogs & derivatives, pharmacology)
• Cell Line, Tumor
• Cell Nucleus (drug effects, enzymology, genetics)
• DNA (antagonists & inhibitors, metabolism)
• Enzyme Activation (drug effects, physiology)
• Humans
• NF-kappa B (antagonists & inhibitors, metabolism)
• Poly Adenosine Diphosphate Ribose (genetics, metabolism)
• Protein Binding (drug effects, physiology)
• Telomerase (biosynthesis, genetics)
• Up-Regulation (drug effects, physiology)