文章：

AV-65是一种新型Wnt/β-catenin信号抑制剂，在小鼠模型中成功抑制多发性骨髓瘤的进展

AV-65, a novel Wnt/β-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model

原文发布日期：2011-11-04

DOI: 10.1038/bcj.2011.41

类型: Original Article

开放获取: 是

英文摘要：

Multiple myeloma (MM) is a malignant neoplasm of plasma cells. Although new molecular targeting agents against MM have been developed based on the better understanding of the underlying pathogenesis, MM still remains an incurable disease. We previously demonstrated that β-catenin, a downstream effector in the Wnt pathway, is a potential target in MM using RNA interference in an in vivo experimental mouse model. In this study, we have screened a library of more than 100 000 small-molecule chemical compounds for novel Wnt/β-catenin signaling inhibitors using a high-throughput transcriptional screening technology. We identified AV-65, which diminished β-catenin protein levels and T-cell factor transcriptional activity. AV-65 then decreased c-myc, cyclin D1 and survivin expression, resulting in the inhibition of MM cell proliferation through the apoptotic pathway. AV-65 treatment prolonged the survival of MM-bearing mice. These findings indicate that this compound represents a novel and attractive therapeutic agent against MM. This study also illustrates the potential of high-throughput transcriptional screening to identify candidates for anticancer drug discovery.

摘要翻译： 

多发性骨髓瘤（MM）是一种浆细胞恶性肿瘤。尽管基于对潜在发病机制的深入理解，已开发出针对MM的新型分子靶向药物，但该疾病目前仍无法治愈。我们先前通过体内小鼠模型中的RNA干扰技术证明，Wnt通路下游效应分子β-连环蛋白是MM的潜在治疗靶点。本研究采用高通量转录筛选技术，从超过10万种小分子化合物库中筛选新型Wnt/β-连环蛋白信号抑制剂。我们鉴定出化合物AV-65，该物质能降低β-连环蛋白水平及T细胞因子转录活性。AV-65随后下调c-myc、细胞周期蛋白D1和生存素表达，通过凋亡途径抑制MM细胞增殖。AV-65治疗延长了荷瘤小鼠的生存期。这些发现表明该化合物是一种极具潜力的新型MM治疗剂。本研究同时印证了高通量转录筛选在抗癌药物研发候选物鉴定中的应用价值。

原文链接：

AV-65, a novel Wnt/β-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model