Cell & Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.
Cell Cycle. 2010 May;9(9):1830-8. doi: 10.4161/cc.9.9.11543. Epub 2010 May 15.
As histone deacetylase inhibitors such as romidepsin (depsipeptide, FK228) complete successful Phase I clinical trials in pediatric solid tumors, it is important that their mechanisms of action are delineated in order to inform the development of subsequent clinical trials as single agents or in combination therapies. In this study, we evaluate the effect of romidepsin as a single agent on a number of different neuroblastoma (NB) cell lines. We find that the growth of 6/6 human NB tumor cell lines but not an immortalized fibroblast cell line (NIH3T3) is inhibited by romidepsin (IC(50) = 1-6.5 ng/ml) after 72 h of treatment. Romidepsin shows selective dose-dependent cytotoxicity in both single copy and N-myc amplified NB cell lines, in cell lines with wild type or mutant p53 and those containing Alk mutations. The decrease in cell proliferation is accompanied by caspase-dependent apoptosis as shown by PARP cleavage, an accumulation of cells in the sub-G(1) phase of the cell cycle and the ability of a pan-caspase inhibitor to reduce cell death. Romidepsin inhibits the growth of subcutaneous NB xenografts in a dose dependent manner in immunocompromised mice. Furthermore, romidepsin induces expression of genes such as p21 and expression of p75 and NTRK (TrkA) which are more highly expressed in the tumors from NB patients that have a good prognosis. These studies support continued investigations into the therapeutic activity of romidepsin in NB.
随着组蛋白去乙酰化酶抑制剂，如罗米地辛（depsipeptide，FK228）在儿科实体瘤的 I 期临床试验中取得成功，明确其作用机制非常重要，以便为后续的单药或联合治疗临床试验提供信息。在这项研究中，我们评估了罗米地辛作为单一药物对多种不同神经母细胞瘤（NB）细胞系的影响。我们发现，罗米地辛（IC50=1-6.5ng/ml）处理 72 小时后，可抑制 6/6 个人类 NB 肿瘤细胞系的生长，但不能抑制永生化成纤维细胞系（NIH3T3）的生长。罗米地辛对单拷贝和 N-myc 扩增的 NB 细胞系、野生型或突变型 p53 细胞系以及含有 Alk 突变的细胞系均表现出选择性的剂量依赖性细胞毒性。细胞增殖的减少伴随着 caspase 依赖性凋亡，表现为 PARP 裂解、细胞周期亚 G1 期的积累以及泛 caspase 抑制剂减少细胞死亡的能力。罗米地辛在免疫功能低下的小鼠中以剂量依赖的方式抑制皮下 NB 异种移植物的生长。此外，罗米地辛诱导 p21 等基因的表达，以及 p75 和 NTRK（TrkA）的表达，这些基因在具有良好预后的 NB 患者的肿瘤中表达更高。这些研究支持对罗米地辛在 NB 中的治疗活性进行进一步研究。
