文章：

基于嵌合和供体来源的风险适应供体淋巴细胞输注治疗儿童白血病

A novel selective small-molecule PI3K inhibitor is effective against human multiple myeloma in vitro and in vivo

原文发布日期：2013-09-06

DOI: 10.1038/bcj.2013.37

类型: Original Article

开放获取: 是

英文摘要：

Developing effective therapies against multiple myeloma (MM) is an unresolved challenge. Phosphatidylinositol-3-kinase (PI3K) activation may be associated with tumor progression and drug resistance, and inhibiting PI3K can induce apoptosis in MM cells. Thus, targeting of PI3K is predicted to increase the susceptibility of MM to anticancer therapy. The lead compound of a novel class of PI3K inhibitors, BAY80-6946 (IC50=0.5 nM against PI3K-α), was highly efficacious in four different MM cell lines, where it induced significant antitumoral effects in a dose-dependent manner. The compound inhibited cell cycle progression and increased apoptosis (P<0.001 compared with controls). Moreover, it abrogated the stimulation conferred by insulin-like growth-factor-1, a mechanism relevant for MM progression. These cellular effects were paralleled by decreased Akt phosphorylation, the main downstream target of PI3K. Likewise, profound antitumoral activity was observed ex vivo, as BAY80-6946 significantly inhibited proliferation of freshly isolated myeloma cells from three patients (P<0.001 compared with vehicle). In addition, BAY80-6946 showed convincing in vivo activity against the human AMO-1 and MOLP-8 myeloma cell lines in a preclinical murine xenograft model, where treatment with 6 mg/kg every other day for 2 weeks reduced the cell numbers by 87.0% and 69.3%, respectively (P<0.001 compared with vehicle), without overt toxicity in treated animals.

摘要翻译： 

开发针对多发性骨髓瘤（MM）的有效疗法仍是一个尚未解决的挑战。磷脂酰肌醇-3-激酶（PI3K）的激活可能与肿瘤进展和耐药性相关，而抑制PI3K可诱导MM细胞凋亡。因此，靶向PI3K预计将增加MM对抗癌治疗的敏感性。新型PI3K抑制剂先导化合物BAY80-6946（对PI3K-α的IC50=0.5 nM）在四种不同MM细胞系中显示出显著疗效，以剂量依赖性方式诱导显著抗肿瘤效应。该化合物能抑制细胞周期进程并增加细胞凋亡（与对照组相比P<0.001）。此外，它还能消除胰岛素样生长因子-1赋予的刺激作用——这是与MM进展相关的重要机制。这些细胞效应伴随着Akt磷酸化（PI3K主要下游靶点）的降低。同样，在离体实验中观察到深度抗肿瘤活性，BAY80-6946显著抑制了三名患者新鲜分离的骨髓瘤细胞增殖（与溶剂对照组相比P<0.001）。在临床前小鼠异种移植模型中，BAY80-6946对人源AMO-1和MOLP-8骨髓瘤细胞系展现出令人信服的体内活性：以6 mg/kg剂量隔日给药治疗两周后，细胞数量分别减少87.0%和69.3%（与溶剂对照组相比P<0.001），且治疗动物未出现明显毒性反应。

原文链接：

A novel selective small-molecule PI3K inhibitor is effective against human multiple myeloma in vitro and in vivo