homoharringtonine and quizartinib

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.

Topics: Adolescent; Adult; Aged, 80 and over; Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Benzothiazoles; Cell Line, Tumor; Drug Delivery Systems; Drug Synergism; Female; fms-Like Tyrosine Kinase 3; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Mice; Mice, Inbred NOD; Mice, Transgenic; Middle Aged; Phenylurea Compounds; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Xenograft Model Antitumor Assays