文章：

双胍多胺类似物维林霉素通过诱导抗酶作用促进神经母细胞瘤的分化

The biguanide polyamine analog verlindamycin promotes differentiation in neuroblastoma via induction of antizyme 

原文发布日期：2021-09-14 

英文摘要：

Deregulated polyamine biosynthesis is emerging as a common feature of neuroblastoma and drugs targeting this metabolic pathway such as DFMO are in clinical and preclinical development. The polyamine analog verlindamycin inhibits the polyamine biosynthesis pathway enzymes SMOX and PAOX, as well as the histone demethylase LSD1. Based on our previous research in acute myeloid leukemia (AML), we reasoned verlindamycin may also unblock neuroblastoma differentiation when combined with all-trans-retinoic acid (ATRA). Indeed, co-treatment with verlindamycin and ATRA strongly induced differentiation regardless of MYCN status, but in MYCN-expressing cells, protein levels were strongly diminished. This process was not transcriptionally regulated but was due to increased degradation of MYCN protein, at least in part via ubiquitin-independent, proteasome-dependent destruction. Here we report that verlindamycin effectively induces the expression of functional tumor suppressor—antizyme via ribosomal frameshifting. Consistent with previous results describing the function of antizyme, we found that verlindamycin treatment led to the selective targeting of ornithine decarboxylase (the rate-limiting enzyme for polyamine biosynthesis) as well as key oncoproteins, such as cyclin D and Aurora A kinase. Retinoid-based multimodal differentiation therapy is one of the few interventions that extends relapse-free survival in MYCN-associated high-risk neuroblastoma and these results point toward the potential use of verlindamycin in this regimen. 

摘要翻译： 

多胺生物合成的失调正逐渐成为神经母细胞瘤的一个共同特征，针对该代谢通路的药物（如DFMO）正处于临床和临床前研发阶段。多胺类似物verlindamycin可抑制多胺生物合成通路中的SMOX和PAOX酶以及组蛋白去甲基化酶LSD1。基于我们先前在急性髓系白血病（AML）中的研究，推测verlindamycin联合全反式维甲酸（ATRA）可能同样能解除神经母细胞瘤的分化阻滞。实验证实，verlindamycin与ATRA联合治疗强烈诱导细胞分化（与MYCN状态无关），但在表达MYCN的细胞中，其蛋白水平显著降低。该过程不受转录调控，而是由于MYCN蛋白降解增强——至少部分通过不依赖泛素、但依赖蛋白酶体的降解机制实现。本研究发现verlindamycin通过核糖体移码机制有效诱导功能性肿瘤抑制因子抗酶（antizyme）的表达。与既往关于抗酶功能的研究一致，verlindamycin治疗可选择性靶向鸟氨酸脱羧酶（多胺生物合成的限速酶）及细胞周期蛋白D、极光激酶A等关键癌蛋白。基于类视黄醇的多模式分化疗法是少数能延长MYCN相关高危神经母细胞瘤无复发生存期的干预措施，本研究结果表明verlindamycin在该治疗方案中具有应用潜力。

原文链接：

The biguanide polyamine analog verlindamycin promotes differentiation in neuroblastoma via induction of antizyme