Natural small molecule triptonide inhibits lethal acute myeloid leukemia with FLT3-ITD mutation by targeting Hedgehog/FLT3 signaling - 19/12/20
páginas | 10 |
Iconografías | 7 |
Vídeos | 0 |
Otros | 0 |
Graphical abstract |
Highlights |
• | Nanomole level of triptonide can induce apoptosis and G0/G1 phase arrest in FLT3-ITD-positive leukemia cells. |
• | Triptonide kills FLT3-ITD-positive acute myeloid leukemia cells through targeting Hedgehog/FLT3 axis. |
• | Triptonide can repress c-Myc and up-regulate p53. |
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.
El texto completo de este artículo está disponible en PDF.Keywords : FLT3-ITD-driven AML, Triptonide, GLI2, Hedgehog signaling, FLT3
Esquema
Vol 133
Artículo 111054- janvier 2021 Regresar al númeroBienvenido a EM-consulte, la referencia de los profesionales de la salud.
El acceso al texto completo de este artículo requiere una suscripción.
Bienvenido a EM-consulte, la referencia de los profesionales de la salud.
La compra de artículos no está disponible en este momento.
¿Ya suscrito a @@106933@@ revista ?