Wu Zhaoxing, Zhuang Haifeng, Yu Qingfeng, Zhang Xuzhao, Jiang Xudong, Lu Xiaoya, Xu Ying, Yang Linlin, Wu Bowen, Ma An, Zhang Lei, Xiao Xibin, Liang Yun, Gao Ruilan, Shen Jianping, Xu Rongzhen
Department of Hematology, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310009, China; Cancer Institute of Zhejiang University, Hangzhou, 310009, China.
Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310009, China.
Transl Oncol. 2019 Jun;12(6):801-809. doi: 10.1016/j.tranon.2019.02.016. Epub 2019 Apr 4.
As a heterogeneous group of clonal disorders, acute myeloid leukemia with internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD) mutation usually shows an inferior prognosis. In the present study, we found that homoharringtonine (HHT), a protein translation inhibitor of plant alkaloid in China, exhibited potent cytotoxic effect against FLT3-ITD (+) cell lines and primary leukemia cells, and a remarkable synergistic anti-leukemia action was demonstrated in vitro and in vivo in xenograft mouse models when co-treated with the heat shock protein 90 inhibitor IPI504. Mechanistically, HHT combined with IPI504 synergistically inhibited the growth of leukemia cells by inducing apoptosis and G1 phase arrest. This synergistic action resulted in a prominent reduction of total and phosphorylated FLT3 (p-FLT3) as well as inhibition of its downstream signaling molecules such as STAT5, AKT, ERK and 4E-BP1. Furthermore, co-treatment of HHT and IPI504 led to a synergistic or additive effect on 55.56%(10/18) of acute myeloid leukemia cases tested, including three relapsed/refractory patients. In conclusion, our findings indicate that the combination of HHT and HSP90 inhibitor provides an alternative way for the treatment of FLT3-ITD positive acute myeloid leukemia, especially for relapsed/refractory AML.
作为一组异质性克隆性疾病，伴有FMS样酪氨酸激酶3（FLT3）内部串联重复突变的急性髓系白血病通常预后较差。在本研究中，我们发现高三尖杉酯碱（HHT），一种中国的植物生物碱蛋白翻译抑制剂，对FLT3-ITD（+）细胞系和原发性白血病细胞表现出强大的细胞毒性作用，并且在异种移植小鼠模型中，与热休克蛋白90抑制剂IPI504联合治疗时，在体外和体内均显示出显著的协同抗白血病作用。机制上，HHT与IPI504联合通过诱导凋亡和G1期阻滞协同抑制白血病细胞的生长。这种协同作用导致总FLT3和磷酸化FLT3（p-FLT3）显著减少，并抑制其下游信号分子如STAT5、AKT、ERK和4E-BP1。此外，HHT和IPI504联合治疗对55.56%（10/18）的测试急性髓系白血病病例产生协同或相加作用，包括3例复发/难治性患者。总之，我们的研究结果表明，HHT与HSP90抑制剂联合为FLT3-ITD阳性急性髓系白血病的治疗提供了一种替代方法，特别是对于复发/难治性急性髓系白血病。
