Tentori L, Balduzzi A, Portarena I, Levati L, Vernole P, Gold B, Bonmassar E, Graziani G
Pharmacology and Medical Oncology Section, Department of Neuroscience, University of Rome Tor Vergata, Via di Tor Vergata 135, 00133 Rome, Italy.
Cell Death Differ. 2001 Aug;8(8):817-28. doi: 10.1038/sj.cdd.4400863.
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.
聚（ADP-核糖）聚合酶（PARP）参与细胞从DNA损伤（如N3-腺嘌呤甲基化）中恢复，这种损伤会激活碱基切除修复过程。在本研究中，我们证明了MeOSO(2)(CH(2))(2)-lexitropsin（Me-Lex），一种几乎只产生N3-甲基腺嘌呤的甲基化剂，根据PARP抑制剂的存在情况，在人白血病细胞系中诱导不同形式的细胞死亡。Me-Lex与PARP抑制剂联合引起的生长抑制与c-myc的显著下调、单链断裂的增加和细胞凋亡有关。当单独用作药物时，在饱和细胞修复能力的浓度下，Me-Lex主要通过坏死诱导细胞死亡。令人惊讶的是，添加PARP抑制剂可增强细胞凋亡并减少坏死的早期出现。单独暴露于Me-Lex的细胞在处理后24小时端粒酶活性完全被抑制，而当Me-Lex与PARP抑制剂联合使用时端粒酶活性没有变化。此后，两种处理均观察到端粒酶受到抑制。这些结果为高浓度N3-甲基腺嘌呤本身或在PARP抑制剂存在下的甲基化碱基诱导的不同细胞死亡形式提供了新的见解。
