Yao Q, Nishiuchi R, Kitamura T, Kersey J H
The Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Leukemia. 2005 Sep;19(9):1605-12. doi: 10.1038/sj.leu.2403881.
17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of the molecular chaperone heat shock protein 90, results in cell type-specific inhibition of proliferation of leukemic cells. GTP14564 is a tyrosine kinase inhibitor actively against FLT3. The current study evaluated the single and combined effects of 17-AAG and GTP14564, and the role of FLT3 in their inhibitory effects. The importance of FLT3 mutations was demonstrated using small interfering RNA (siRNA) targeted to FLT3. Similar to FLT3 siRNA, GTP14564 inhibited FLT3 internal tandem duplication (ITD) cells (MV4;11) and FLT3 amplified wild-type cells (SEMK2-M1), but not wild-type FLT3 cells (RS4;11). However, when RS4;11 cells were stimulated with FLT3-ligand, phosphorylation of STAT5 and GTP14564 inhibition were observed. Responses to GTP14564 in all cell types were directly related to the level of STAT5 phosphorylation in the cells. We observed synergistic effects of combined 17-AAG and GTP14564 in cell lines with FLT3-ITD and amplified wild-type FLT3. Combined treatment with 17-AAG and GTP14564 reduced the levels of p-FLT3 and p-STAT5, enhanced G0/G1 arrest and apoptosis in FLT3-ITD and amplified wild-type FLT3. The combination of 17-AAG with FLT3 kinase inhibitors can enhance targeted therapy in leukemias with FLT3 mutations, such as MLL fusion gene leukemias.
17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）是分子伴侣热休克蛋白90的抑制剂，可导致白血病细胞增殖的细胞类型特异性抑制。GTP14564是一种对FLT3有效的酪氨酸激酶抑制剂。本研究评估了17-AAG和GTP14564的单一及联合作用，以及FLT3在其抑制作用中的作用。使用靶向FLT3的小干扰RNA（siRNA）证明了FLT3突变的重要性。与FLT3 siRNA相似，GTP14564抑制FLT3内部串联重复（ITD）细胞（MV4;11）和FLT3扩增的野生型细胞（SEMK2-M1），但不抑制野生型FLT3细胞（RS4;11）。然而，当用FLT3配体刺激RS4;11细胞时，观察到STAT5磷酸化和GTP14564抑制。所有细胞类型对GTP14564的反应与细胞中STAT5磷酸化水平直接相关。我们观察到17-AAG和GTP14564联合使用对具有FLT3-ITD和扩增野生型FLT3的细胞系有协同作用。17-AAG和GTP14564联合治疗降低了p-FLT3和p-STAT5的水平，增强了FLT3-ITD和扩增野生型FLT3的G0/G1期阻滞和凋亡。17-AAG与FLT3激酶抑制剂联合使用可增强对具有FLT3突变的白血病（如MLL融合基因白血病）的靶向治疗。
