Background/Objectives: Neuroblastoma (NB) is an aggressive pediatric malignancy that accounts for nearly 15% of all childhood cancer-related deaths, with high-risk cases showing a poor 20% prognosis and limited response to current therapies. Survivin, encoded by theBIRC5gene, is an anti-apoptotic protein frequently overexpressed in NB and linked to treatment resistance and unfavorable clinical outcomes. Methods and Results: An analysis of 1235 NB patient datasets revealed a significant association between elevatedBIRC5expression and reduced overall and event-free survival, highlighting survivin as an important therapeutic target in NB. To explore this strategy, we evaluated the efficacy of YM-155, a small-molecule survivin inhibitor, across multiple NB cell lines. YM-155 displayed potent cytotoxic activity in six NB cell lines with IC50values ranging from 8 to 212 nM and significantly inhibited colony formation and 3D spheroid growth in a dose-dependent manner. Mechanistic analyses revealed that YM-155 downregulated survivin at both mRNA and protein levels, induced apoptosis by about 2–7-fold, and caused G0/G1 phase cell cycle arrest. Moreover, YM-155 treatment enhanced p53 expression, suggesting reactivation of tumor suppressor pathways. Notably, combining YM-155 and the chemotherapeutic agent etoposide resulted in synergistic inhibition of NB growth with ED75 values ranging from 0.17 to 1, compared to either agent alone. In the xenograft mouse model, YM-155 inhibited tumor burden in contrast to controls by about 3-fold, and without any notable toxic effects in vivo. Conclusion: Overall, our findings identify YM-155 as a promising therapeutic agent for high-risk NB by directly targeting survivin and enhancing chemosensitivity. These results support continued preclinical development of survivin inhibitors as part of rational combination strategies in pediatric cancer treatment.
背景/目的：神经母细胞瘤（NB）是一种侵袭性儿童恶性肿瘤，约占所有儿童癌症相关死亡的15%，其中高危病例预后较差（生存率仅20%），且对现有疗法反应有限。由BIRC5基因编码的生存素是一种抗凋亡蛋白，在NB中常过度表达，并与治疗耐药及不良临床结局相关。方法与结果：通过对1235例NB患者数据集的分析发现，BIRC5表达升高与总生存期和无事件生存期缩短显著相关，提示生存素是NB的重要治疗靶点。为探索这一策略，我们评估了小分子生存素抑制剂YM-155在多种NB细胞系中的疗效。YM-155在6种NB细胞系中显示出强效细胞毒性活性，IC50值范围为8-212 nM，并以剂量依赖方式显著抑制集落形成和3D球体生长。机制分析表明，YM-155在mRNA和蛋白水平下调生存素表达，诱导约2-7倍的细胞凋亡，并引起G0/G1期细胞周期阻滞。此外，YM-155处理增强了p53表达，提示肿瘤抑制通路被重新激活。值得注意的是，YM-155与化疗药物依托泊苷联用对NB生长产生协同抑制作用（ED75值范围为0.17-1），效果优于单药治疗。在异种移植小鼠模型中，YM-155使肿瘤负荷较对照组降低约3倍，且未观察到明显的体内毒性效应。结论：本研究证实YM-155通过直接靶向生存素并增强化疗敏感性，有望成为高危NB的潜在治疗药物。这些结果为继续推进生存素抑制剂作为儿童癌症合理化联合治疗策略的临床前研究提供了依据。
Striking at Survivin: YM-155 Inhibits High-Risk Neuroblastoma Growth and Enhances Chemosensitivity
肿瘤(癌症)患者之家