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, L., Forini, O., Fossile, E., Muzi, A., Vergati, M., Portarena, I., et al. (2005). N3-methyladenine induces early poly(ADP-ribosylation), reduction of nuclear factor-kappa B DNA binding ability, and nuclear up-regulation of telomerase activity. MOLECULAR PHARMACOLOGY [10.1124/mol.104.004937].

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

TENTORI, LUCIO;AMICI, CARLA;GRAZIANI, GRAZIA
2005-01-01

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.
2005
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/14 - FARMACOLOGIA
English
Con Impact Factor ISI
N3-methyladenine; O6-methylguanine; temozolomide; N-methyl-N′-nitro-N-nitrosoguanidine; methyl nitrosourea; base excision repair;O6-alkylguanine DNA alkyltransferase; mismatch repair system; MeOSO2(CH2)2-lexitropsin;N-methylpurine-DNA glycosylase; poly(ADP-ribose) polymerase-1; nuclear factor-κB; 3-aminobenzamide; 8-hydroxy-2-methylquinazolin-4[3H]one; reactive oxygen species; Iκ kinase; telomeric repeats amplification protocol; apoptosis-inducing factor
Tentori, L., Forini, O., Fossile, E., Muzi, A., Vergati, M., Portarena, I., et al. (2005). N3-methyladenine induces early poly(ADP-ribosylation), reduction of nuclear factor-kappa B DNA binding ability, and nuclear up-regulation of telomerase activity. MOLECULAR PHARMACOLOGY [10.1124/mol.104.004937].
Tentori, L; Forini, O; Fossile, E; Muzi, A; Vergati, M; Portarena, I; Amici, C; Gold, B; Graziani, G
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/40457
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