Department of Paediatric Haematology and Oncology, University Children's Hospital, Muenster, Germany.
Anticancer Drugs. 2011 Jul;22(6):531-42. doi: 10.1097/CAD.0b013e3283454526.
Polo-like kinase 1 (PLK1) is a regulator of mitosis and its upregulation in tumours is often associated with poor prognosis. Although PLK1 inhibitors have already entered phase 1 clinical trials, little is known about their impact on the treatment of paediatric malignancies. Thus, we evaluated the concept of PKL1 inhibition by testing the effects of the PLK1 inhibitor GW843682X alone and in combination with the topoisomerase 1 inhibitor, camptothecin, against a panel of 18 paediatric tumour cell lines. Cytotoxicity was evaluated by MTT test and by caspase 3/7 activation. Expression of target was confirmed by western blot analysis. Expression of ATP binding cassette transporters was analysed by quantitative real-time reverse transcription PCR. GW843682X significantly inhibited cell growth in all 18 cell lines. Concentrations, which inhibited cell growth by 50% compared with untreated controls after 72 h, ranged from 0.02 to 11.7 μmol/l. Apart from the N-Myc-amplified neuroblastoma cell lines, the osteosarcoma cell lines MNNG-HOS and OST, which are highly resistant to standard anticancer drugs, were sensitive to GW843682X. The toxicity of GW843682X was dependent neither on the ATP binding cassette drug transporter expression nor on the p53 mutation status. Neither synergistic nor antagonistic effects were observed for the combination of GW843682X and camptothecin in 14 cell lines. GW843682X showed considerable toxicity against a panel of paediatric tumour cell lines suggesting that PLK1 inhibitors under clinical development should be evaluated against paediatric malignancies too.
丝氨酸/苏氨酸激酶 polo 样激酶 1（PLK1）是有丝分裂的调节因子，其在肿瘤中的上调通常与预后不良有关。尽管 PLK1 抑制剂已经进入 1 期临床试验，但对于它们对儿科恶性肿瘤治疗的影响知之甚少。因此，我们通过测试 PLK1 抑制剂 GW843682X 单独使用以及与拓扑异构酶 1 抑制剂喜树碱联合使用对 18 种儿科肿瘤细胞系的作用，评估了 PLK1 抑制的概念。通过 MTT 试验和 caspase 3/7 激活评估细胞毒性。通过 Western blot 分析确认靶蛋白的表达。通过定量实时逆转录 PCR 分析 ATP 结合盒转运蛋白的表达。GW843682X 显著抑制了所有 18 种细胞系的细胞生长。与未经处理的对照相比，在 72 小时后抑制细胞生长 50%的浓度范围为 0.02 至 11.7 μmol/l。除了 N-Myc 扩增的神经母细胞瘤细胞系外，对标准抗癌药物高度耐药的骨肉瘤细胞系 MNNG-HOS 和 OST 对 GW843682X 也敏感。GW843682X 的毒性既不依赖于 ATP 结合盒药物转运蛋白的表达，也不依赖于 p53 突变状态。在 14 种细胞系中，GW843682X 与喜树碱联合使用没有观察到协同或拮抗作用。GW843682X 对一组儿科肿瘤细胞系表现出相当大的毒性，这表明处于临床开发阶段的 PLK1 抑制剂也应针对儿科恶性肿瘤进行评估。
