Blood Cancer J. 2011 Nov;1(11):e43. doi: 10.1038/bcj.2011.41. Epub 2011 Nov 4.
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.
多发性骨髓瘤（MM）是一种浆细胞的恶性肿瘤。尽管基于对发病机制的更好理解，已经开发出了针对 MM 的新的分子靶向药物，但 MM 仍然是一种无法治愈的疾病。我们之前使用体内实验小鼠模型中的 RNA 干扰证明了 Wnt 通路下游效应子β-catenin 是 MM 的一个潜在靶点。在这项研究中，我们使用高通量转录筛选技术筛选了超过 100000 种小分子化合物文库，以寻找新的 Wnt/β-catenin 信号抑制剂。我们鉴定出了 AV-65，它可以降低β-catenin 蛋白水平和 T 细胞因子转录活性。AV-65 随后降低了 c-myc、cyclin D1 和 survivin 的表达，通过凋亡途径抑制 MM 细胞增殖。AV-65 治疗延长了 MM 荷瘤小鼠的生存时间。这些发现表明该化合物代表了一种针对 MM 的新型有吸引力的治疗剂。这项研究还说明了高通量转录筛选在发现抗癌药物候选物方面的潜力。
