Department of Hematology/Oncology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8510, Japan.
Leukemia. 2010 Jan;24(1):33-43. doi: 10.1038/leu.2009.212. Epub 2009 Oct 15.
Treatment using Fms-like tyrosine kinase-3 (FLT3) inhibitors is a promising approach to overcome the dismal prognosis of acute myeloid leukemia (AML) with activating FLT3 mutations. Current trials are combining FLT3 inhibitors with p53-activating conventional chemotherapy. The mechanisms of cytotoxicity of FLT3 inhibitors are poorly understood. We investigated the interaction of FLT3 and p53 pathways after their simultaneous blockade using the selective FLT3 inhibitor FI-700 and the MDM2 inhibitor Nutlin-3 in AML. We found that FI-700 immediately reduced antiapoptotic Mcl-1 levels and enhanced Nutlin-induced p53-mediated mitochondrial apoptosis in FLT3/internal tandem duplication cells through the Mcl-1/Noxa axis. FI-700 induced proteasome-mediated degradation of Mcl-1, resulting in the reduced ability of Mcl-1 to sequester proapoptotic Bim. Nutlin-3 induced Noxa, which displaced Bim from Mcl-1. The FI-700/Nutlin-3 combination profoundly activated Bax and induced apoptosis. Our findings suggest that FI-700 actively enhances p53 signaling toward mitochondrial apoptosis and that a combination strategy aimed at inhibiting FLT3 and activating p53 signaling could potentially be effective in AML.
使用 Fms 样酪氨酸激酶-3（FLT3）抑制剂的治疗方法是克服具有激活 FLT3 突变的急性髓性白血病（AML）预后不良的有希望的方法。目前的试验将 FLT3 抑制剂与激活 p53 的常规化疗联合使用。FLT3 抑制剂的细胞毒性机制尚不清楚。我们使用选择性 FLT3 抑制剂 FI-700 和 MDM2 抑制剂 Nutlin-3 同时阻断 FLT3 和 p53 途径后，研究了它们在 AML 中的相互作用。我们发现，FI-700 通过 Mcl-1/Noxa 轴立即降低抗凋亡 Mcl-1 水平，并增强 Nutlin 诱导的 FLT3/内部串联重复细胞中的 p53 介导的线粒体凋亡。FI-700 诱导 Mcl-1 的蛋白酶体介导的降解，导致 Mcl-1 隔离促凋亡 Bim 的能力降低。Nutlin-3 诱导 Noxa，从而将 Bim 从 Mcl-1 中置换出来。FI-700/Nutlin-3 联合显着激活 Bax 并诱导细胞凋亡。我们的研究结果表明，FI-700 积极增强了 p53 信号向线粒体凋亡的作用，并且旨在抑制 FLT3 和激活 p53 信号的联合策略在 AML 中可能是有效的。
