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. 2021 Jun:188:114538.
doi: 10.1016/j.bcp.2021.114538. Epub 2021 Apr 6.

Homoharringtonine synergizes with quizartinib in FLT3-ITD acute myeloid leukemia by targeting FLT3-AKT-c-Myc pathway

Fangfang Wang  1 , Jingcao Huang  1 , Tingting Guo  2 , Yuhuan Zheng  1 , Li Zhang  1 , Dan Zhang  1 , Fujue Wang  1 , Duolan Naren  3 , Yushan Cui  1 , Xiaoyan Liu  1 , Ying Qu  1 , Hongmei Luo  1 , Yan Yang  1 , Haichen Wei  1 , Yong Guo  4
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Homoharringtonine synergizes with quizartinib in FLT3-ITD acute myeloid leukemia by targeting FLT3-AKT-c-Myc pathway

Fangfang Wang et al. Biochem Pharmacol. 2021 Jun.

Abstract

Acute myeloid leukemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) has a dismal prognosis. FLT3 inhibitors have been developed to treat patients with FLT3-ITD AML; however, when used alone, their efficacy is insufficient. FLT3 inhibitors combined with chemotherapy may be a promising treatment for FLT3-ITD AML. Homoharringtonine (HHT) is a classical anti-leukaemia drug with high sensitivity to FLT3-ITD AML cells. Here, we showed that HHT synergizes with a selective next-generation FLT3 inhibitor, quizartinib, to inhibit cell growth/viability and induce cell-cycle arrest and apoptosis in FLT3-ITD AML cells in vitro, significantly inhibit acute myeloid leukemia progression in vivo, and substantially prolong survival of mice-bearing human FLT3-ITD AML. Mechanistically, HHT and quizartinib cooperatively inhibit FLT3-AKT and its downstream targets GSK3β, c-Myc, and cyclin D1, cooperatively up-regulate the pro-apoptosis proteins Bim and Bax, and down-regulate the anti-apoptosis protein Mcl1. Most strikingly, HHT and quizartinib cooperatively reduce the numbers of side-population (SP) and aldehyde dehydrogenase (ALDH)-positive cells, which reportedly are rich in LSCs. In conclusion, HHT combined with quizartinib may be a promising treatment strategy for patients with FLT3-ITD AML.

Keywords: Acute myeloid leukemia; FLT3 internal tandem duplication; Homoharringtonine; Quizartinib.

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