Gruber Beata M, Anuszewska Elzbieta L, Bubko Irena, Gozdzik Aneta, Priebe Waldemar, Fokt Izabela
National Institute of Public Health, Department of Biochemistry and Biopharmaceuticals, Chelmska 30/34 Str., 00-725 Warsaw, Poland.
Anticancer Res. 2005 May-Jun;25(3B):2193-8.
The use of anthracyclines as antitumor drugs dates back to the 1970s, but the mechanism of the cytotoxicity of these compounds has long been a matter of debate. There is increasing evidence indicating that drug-induced cytotoxicity commonly converges on the induction of apoptosis. Many authors point to the fact that double-strand breaks, resulting from stabilization of cleavable complexes, are the signal for the initiation of the apoptotic cascade. In this work, the possible correlation between stabilization of topoisomerase II (topoII)-DNA complexes, apoptosis induction and cytotoxicity was studied. Parental human cervix carcinoma cells, HeLa, and its subline resistant to vinblastine, KB-V1, were exposed to doxorubicin (DOX) and the novel anthracyclines annamycin and WP903, given at the concentrations 0.2 and 2.0 microg/ml (DOX and annamycin) or 0.2 and 1.0 microg/ml (WP903). It was found that annamycin was the strongest topoII poison in HeLa cells at both concentrations used, whereas poly (ADP-ribose) polymerase (PARP) cleavage was observed dose-dependently in KB-V1 cells treated with annamycin or WP903. Simultaneously, apoptosis, observed as cell morphology or phosphatidylserine translocation, was evident in both cell types exposed to the novel anthracyclines, independent of concentration. DOX appeared to be the weakest apoptotic inducer. On the basis of these studies, it can be suggested that topoII poisoning is not the key process leading to apoptosis and seems to be cell specific. PARP cleavage is probably not an evident marker of anthracycline-induced apoptosis which, in turn, does not seem to be the determinant in the cytotoxic action of these compounds. The efficiency of anthracycline antibiotics, interpreted as cytotoxic action, was dependent on cell type.
蒽环类药物作为抗肿瘤药物的使用可追溯到20世纪70年代，但这些化合物的细胞毒性机制长期以来一直存在争议。越来越多的证据表明，药物诱导的细胞毒性通常集中在诱导细胞凋亡上。许多作者指出，可裂解复合物的稳定导致的双链断裂是凋亡级联反应启动的信号。在这项工作中，研究了拓扑异构酶II（topoII）-DNA复合物的稳定、凋亡诱导和细胞毒性之间的可能相关性。将亲本人类宫颈癌细胞HeLa及其对长春碱耐药的亚系KB-V1暴露于阿霉素（DOX）以及新型蒽环类药物安那霉素和WP903，浓度分别为0.2和2.0微克/毫升（DOX和安那霉素）或0.2和1.0微克/毫升（WP903）。结果发现，在所使用的两种浓度下，安那霉素都是HeLa细胞中最强的topoII毒物，而在用安那霉素或WP903处理的KB-V1细胞中观察到聚（ADP-核糖）聚合酶（PARP）的切割呈剂量依赖性。同时，在暴露于新型蒽环类药物的两种细胞类型中，以细胞形态或磷脂酰丝氨酸易位观察到的细胞凋亡是明显的，与浓度无关。DOX似乎是最弱的凋亡诱导剂。基于这些研究，可以认为topoII中毒不是导致细胞凋亡的关键过程，似乎具有细胞特异性。PARP切割可能不是蒽环类药物诱导细胞凋亡的明显标志物，而细胞凋亡反过来似乎也不是这些化合物细胞毒性作用的决定因素。蒽环类抗生素的效率，解释为细胞毒性作用，取决于细胞类型。
