Tanaka Y, Yoshihara K, Tohno Y, Kojima K, Kameoka M, Kamiya T
Department of Biochemistry, Nara Medical University, Japan.
Cell Mol Biol (Noisy-le-grand). 1995 Sep;41(6):771-81.
In a previous report we described that adenosine-induced apoptosis of HL-60 cells was blocked by the pretreatment of cells with a potent inhibitor (3-aminobenzamide) of poly(ADP-ribose) polymerase (PARP). The pretreatment of the cells with nicotinamide, another inhibitor of the enzyme, also suppressed most effectively the adenosine-induced apoptosis. This inhibition was reversible and observed during apoptosis mediated by other known apoptosis inducers such as actinomycin D and staurosporine (group I inducers), but nicotinamide was ineffective on the apoptosis mediated by VM 26, camptothecin and A23187 (group II inhibitors). In addition to the enzyme inhibition, a down-regulation of the enzyme level caused by the pretreatments of cells with differentiation-inducing agents, retinoic acid (RA) and dimethylsulfoxide (DMSO) also resulted in a marked resistance of the cells to the apoptosis inducers. A pretreatment of the cells for a limited time of 24 hrs. by these agents decreased the PARP level to 66-75% of the untreated cells and the cells showed a quite similar resistance to the group I apoptosis inducers like the cells treated with the enzyme inhibitors, whereas they were still sensitive to the group II inhibitors. A more prolonged treatment for 48 hrs. of the cells with RA and DMSO resulted in further down-regulation of the cellular PARP reaching respectively 50 and 43% of control cells and at this stage, the cells became resistant to all the inducers of both groups. These results suggest that the pathway, by which both groups of the inducers initiate and progress apoptosis, is not identical but include at least two different processes which are differently affected by PARP-inhibition or by different levels of cellular PARP.
在之前的一份报告中，我们描述了用聚（ADP - 核糖）聚合酶（PARP）的强效抑制剂（3 - 氨基苯甲酰胺）预处理细胞可阻断腺苷诱导的HL - 60细胞凋亡。用该酶的另一种抑制剂烟酰胺预处理细胞，也能最有效地抑制腺苷诱导的凋亡。这种抑制是可逆的，并且在由其他已知凋亡诱导剂如放线菌素D和星形孢菌素（I组诱导剂）介导的凋亡过程中也能观察到，但烟酰胺对由VM 26、喜树碱和A23187（II组抑制剂）介导的凋亡无效。除了酶抑制作用外，用分化诱导剂视黄酸（RA）和二甲基亚砜（DMSO）预处理细胞导致酶水平下调，这也使细胞对凋亡诱导剂产生显著抗性。用这些试剂对细胞进行24小时的有限时间预处理，可使PARP水平降至未处理细胞的66 - 75%，并且这些细胞对I组凋亡诱导剂的抗性与用酶抑制剂处理的细胞相当，而它们对II组抑制剂仍敏感。用RA和DMSO对细胞进行更长时间的48小时处理，导致细胞PARP进一步下调，分别达到对照细胞的50%和43%，在此阶段，细胞对两组诱导剂均产生抗性。这些结果表明，两组诱导剂启动和促进凋亡的途径并不相同，但至少包括两个不同的过程，PARP抑制或细胞PARP的不同水平对这两个过程有不同影响。
