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Molecular Pharmacology

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Research ArticleORIGINAL ARTICLE

N3-Methyladenine Induces Early Poly(ADP-Ribosylation), Reduction of Nuclear Factor-κB DNA Binding Ability, and Nuclear Up-Regulation of Telomerase Activity

Lucio Tentori, Olindo Forini, Emanuela Fossile, Alessia Muzi, Matteo Vergati, Ilaria Portarena, Carla Amici, Barry Gold and Grazia Graziani
Molecular Pharmacology February 2005, 67 (2) 572-581; DOI: https://doi.org/10.1124/mol.104.004937
Lucio Tentori
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Olindo Forini
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Emanuela Fossile
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Alessia Muzi
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Matteo Vergati
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Ilaria Portarena
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Carla Amici
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Barry Gold
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Grazia Graziani
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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 MeOSO2 (CH2)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-κB (NF-κB) 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-κB 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.

  • Received July 13, 2004.
  • Accepted November 16, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 67 (2)
Molecular Pharmacology
Vol. 67, Issue 2
1 Feb 2005
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Research ArticleORIGINAL ARTICLE

N3-Methyladenine Induces Early Poly(ADP-Ribosylation), Reduction of Nuclear Factor-κB DNA Binding Ability, and Nuclear Up-Regulation of Telomerase Activity

Lucio Tentori, Olindo Forini, Emanuela Fossile, Alessia Muzi, Matteo Vergati, Ilaria Portarena, Carla Amici, Barry Gold and Grazia Graziani
Molecular Pharmacology February 1, 2005, 67 (2) 572-581; DOI: https://doi.org/10.1124/mol.104.004937

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Research ArticleORIGINAL ARTICLE

N3-Methyladenine Induces Early Poly(ADP-Ribosylation), Reduction of Nuclear Factor-κB DNA Binding Ability, and Nuclear Up-Regulation of Telomerase Activity

Lucio Tentori, Olindo Forini, Emanuela Fossile, Alessia Muzi, Matteo Vergati, Ilaria Portarena, Carla Amici, Barry Gold and Grazia Graziani
Molecular Pharmacology February 1, 2005, 67 (2) 572-581; DOI: https://doi.org/10.1124/mol.104.004937
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