文章：

DHODH抑制在新型体内斑马鱼模型中抑制MYC并阻碍髓母细胞瘤生长

DHODH Inhibition SuppressesMYCand Inhibits the Growth of Medulloblastoma in a Novel In Vivo Zebrafish Model

原文发布日期：13 December 2024

DOI: 10.3390/cancers16244162

类型: Article

开放获取: 是

英文摘要：

Background/Objectives: Medulloblastoma (MB) is the most common high-grade paediatric brain tumour, with group 3 MB patients having the worst prognosis. A high prevalence of group 3 tumours shows overexpression of theMYConcogene, making it a potential therapeutic target. However, attempts to directly inhibitMYChave so far demonstrated limited success. Dihydroorotate dehydrogenase (DHODH), a crucial enzyme of the pyrimidine biosynthesis process, has emerged as an up-and-coming target in oncology, as its inhibition has shown promise in several cancers. Methods: In this study, we investigated the efficacy of brequinar, a DHODH inhibitor, in MB, with a focus on group 3. In vitro, BRQ’s effects on cell viability and MYC expression were tested in seven MB cell lines. In vivo, a novel zebrafish xenograft model was used to evaluate BRQ’s impact on tumour growth and toxicity. Results: HighDHODHexpression was identified in group 3 and shh MB subgroups, correlating with poor survival andMYCexpression. BRQ demonstrated nanomolar efficacy in inducing apoptosis and reducingMYCexpression in group 3 MB cell lines. Finally, we established a novel zebrafish xenograft model and demonstrated that BRQ significantly inhibited tumour growth at non-toxic concentrations in vivo, particularly in the D458 metastatic MB cell line. Conclusions: Our findings indicate that DHODH is a promising therapeutic target in group 3 MBs. Furthermore, BRQ shows potential for clinical application, effectively reducing tumour growth andMYCexpression in vitro and in vivo. Moreover, our newly established zebrafish xenograft model offers a promising avenue for rapid in vivo drug testing for use in MB.

摘要翻译： 

背景/目的：髓母细胞瘤（MB）是最常见的高级别儿童脑肿瘤，其中第3组MB患者预后最差。该组肿瘤中MYC原癌基因过表达现象普遍，使其成为潜在治疗靶点。然而，直接抑制MYC的尝试迄今成效有限。二氢乳清酸脱氢酶（DHODH）作为嘧啶生物合成过程的关键酶，已成为肿瘤学领域新兴靶点，其抑制剂在多种癌症治疗中展现出潜力。方法：本研究探讨了DHODH抑制剂布雷奎纳（BRQ）在MB（特别是第3组）中的疗效。在体外实验中，通过七种MB细胞系检测BRQ对细胞活力及MYC表达的影响；在体内实验中，采用新型斑马鱼异种移植模型评估BRQ对肿瘤生长及毒性的作用。结果：在第3组和SHH亚型MB中发现DHODH高表达，且与不良预后及MYC表达相关。BRQ在纳摩尔浓度下即可诱导第3组MB细胞系凋亡并降低MYC表达。通过新型斑马鱼异种移植模型证实，BRQ在无毒浓度下能显著抑制体内肿瘤生长，尤其在D458转移性MB细胞系中效果显著。结论：DHODH是第3组MB极具前景的治疗靶点，BRQ在体内外均能有效抑制肿瘤生长并降低MYC表达，具备临床应用潜力。本研究建立的斑马鱼异种移植模型为MB药物快速体内测试提供了新途径。

原文链接：

DHODH Inhibition SuppressesMYCand Inhibits the Growth of Medulloblastoma in a Novel In Vivo Zebrafish Model