Shikonin Exerts an Antileukemia Effect against FLT3-ITD Mutated Acute Myeloid Leukemia Cells via Targeting FLT3 and Its Downstream Pathways

Abstract

<b><i>Introduction:</i></b> Acute myeloid leukemia (AML) with internal tandem duplication (ITD) mutations in Fms-like tyrosine kinase 3 (FLT3) has an unfavorable prognosis. Recently, using newly emerging inhibitors of FLT3 has led to improved outcomes of patients with <i>FLT3</i>-ITD mutations. However, drug resistance and relapse continue to be significant challenges in the treatment of patients with <i>FLT3</i>-ITD mutations. This study aimed to evaluate the antileukemic effects of shikonin (SHK) and its mechanisms of action against AML cells with <i>FLT3</i>-ITD mutations in vitro and in vivo. <b><i>Methods:</i></b> The CCK-8 assay was used to analyze cell viability, and flow cytometry was used to detect cell apoptosis and differentiation. Western blotting and real-time polymerase chain reaction were used to examine the expression of certain proteins and genes. Leukemia mouse model was created to evaluate the antileukemia effect of SHK against <i>FLT3</i>-ITD mutated leukemia in vivo. <b><i>Results:</i></b> After screening a series of leukemia cell lines, those with <i>FLT3</i>-ITD mutations were found to be more sensitive to SHK in terms of proliferation inhibition and apoptosis induction than those without <i>FLT3</i>-ITD mutation. SHK suppresses the expression and phosphorylation of FLT3 receptors and their downstream molecules. Inhibition of the NF-κB/miR-155 pathway is an important mechanism through which SHK kills FLT3-AML cells. Moreover, a low concentration of SHK promotes the differentiation of AML cells with <i>FLT3</i>-ITD mutations. Finally, SHK could significantly inhibit the growth of MV4-11 cells in leukemia bearing mice. <b><i>Conclusion:</i></b> The findings of this study indicate that SHK may be a promising drug for the treatment of <i>FLT3</i>-ITD mutated AML.