2. Academic Validation
  3. Homoharringtonine Combined with the Heat Shock Protein 90 Inhibitor IPI504 in the Treatment of FLT3-ITD Acute Myeloid Leukemia

Homoharringtonine Combined with the Heat Shock Protein 90 Inhibitor IPI504 in the Treatment of FLT3-ITD Acute Myeloid Leukemia

  • Transl Oncol. 2019 Jun;12(6):801-809. doi: 10.1016/j.tranon.2019.02.016.
Zhaoxing Wu 1,  Haifeng Zhuang 2,  Qingfeng Yu 1,  Xuzhao Zhang 3,  Xudong Jiang 4,  Xiaoya Lu 1,  Ying Xu 1,  Linlin Yang 1,  Bowen Wu 1,  An Ma 5,  Lei Zhang 1,  Xibin Xiao 3,  Yun Liang 3,  Ruilan Gao 2,  Jianping Shen 6,  Rongzhen Xu 7
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310009, China.
  • 3 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.
  • 4 Department of Geriatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 5 Zhejiang Academy of Medical Sciences, Hangzhou, 310009, China.
  • 6 Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310009, China. Electronic address: zrxyk10@zju.edu.cn.
  • 7 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. Electronic address: zrxyk10@zju.edu.cn.
PMID: 30953928 DOI: 10.1016/j.tranon.2019.02.016
Abstract

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.

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