Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Leuk Res. 2010 Apr;34(4):535-41. doi: 10.1016/j.leukres.2009.07.043. Epub 2009 Sep 1.
We have previously shown that inhibition of translation initiation, using the small molecule inhibitor silvestrol, induces apoptosis in a pre-clinical murine lymphoma model when combined with daunorubicin. Silvestrol blocks ribosome recruitment by targeting the RNA helicase, eIF4A, which is required for this process. Here we investigate the sensitivity of acute myelogenous leukemia (AML) cell lines to protein synthesis inhibition in combination with the standard cytotoxic agents daunorubicin, etoposide, and cytarabine. Silvestrol shows synergy with standard-of-care agents in AML cell lines and synergizes with ABT-737, a small molecule inhibitor of Bcl-X(L) and Bcl-2. The in vitro synergy between silvestrol and the cytotoxic drugs used in AML therapy provides a basis for in vivo evaluation of these combinations.
我们之前已经表明，当与柔红霉素联合使用时，使用小分子抑制剂 silvestrol 抑制翻译起始会在临床前鼠淋巴瘤模型中诱导细胞凋亡。Silvestrol 通过靶向 RNA 解旋酶 eIF4A 来阻止核糖体募集，这是该过程所必需的。在这里，我们研究了急性髓细胞白血病 (AML) 细胞系对与标准细胞毒性药物柔红霉素、依托泊苷和阿糖胞苷联合使用的蛋白质合成抑制的敏感性。Silvestrol 与 AML 细胞系中的标准治疗药物具有协同作用，并与 ABT-737 协同作用，ABT-737 是 Bcl-X(L) 和 Bcl-2 的小分子抑制剂。Silvestrol 与 AML 治疗中使用的细胞毒性药物的体外协同作用为这些组合的体内评估提供了基础。
