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  • Title: Natural small molecule triptonide inhibits lethal acute myeloid leukemia with FLT3-ITD mutation by targeting Hedgehog/FLT3 signaling.
    Author: Xu Y, Wang P, Li M, Wu Z, Li X, Shen J, Xu R.
    Journal: Biomed Pharmacother; 2021 Jan; 133():111054. PubMed ID: 33254022.
    Abstract:
    Acute myeloid leukemia harboring internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-ITD AML) is a subset of highly aggressive malignancies with poor clinical outcome. Despite some advances in the development of FLT3 tyrosine kinase inhibitors (FLT3 inhibitors), most of FLT3-ITD AML patients suffer from lethal disease relapse, suggesting the requirement of novel targets and agents. Here we describe a natural small molecule, triptonide that can efficiently inhibit FLT3-ITD-driven AML in vitro and in vivo. Mechanistically, triptonide targeted Hedgehog/FLT3 signaling by inhibiting its critical effectors, which are GLI2, c-Myc and FLT3 and induced apoptosis of FLT3-ITD-driven leukemia cells. In addition, we also observed that triptonide activated tumor suppressor p53. In vivo, triptonide treatment markedly suppressed lethal FLT3-ITD-driven AML with good tolerance and prolonged survival time in orthotopic mouse model. Our studies identify Hedgehog/FLT3 axis as a novel target for treating FLT3-ITD-driven leukemia and demonstrate that triptonide is an active lead compound that can kill FLT3-ITD-driven leukemia cells.
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