Luteoloside inhibits proliferation, induces apoptosis and differentiation via ß-catenin/c-Myc axis in acute myeloid leukemia

Background: Acute myeloid leukemia (AML) is the most common leukemia in adults, that has a poor prognosis due in part to low response to treatment and high recurrence. And drugs commonly used in conventional treatment strategies often cause serious side-effects. Purpose: To investigate the high efficacy and low toxicity of luteoloside on AML and explore its mechanism of action. Methods:The proliferation of AML cells treated with different concentrations of luteoloside was assessed by the CCK-8 assay and colony formation assay, and apoptosis and differentiation were detected by flow cytometry. RNA-Seq analysis and western blotting were performed to explore the mechanism by which luteoloside exerted anti-AML effects. The patient-derived xenografts (PDX) model was established to assess anti-AML effect of luteoloside in vivo, and construction of an orthotopic AML mouse model explored the combination therapy of luteoloside and cytarabine. Results: Herein, we found that luteoloside could dramatically impair the proliferation and clonogenic capacity of AML cells and induce S phase arrest associated with decrease of Cyclin D1 and increase of Cyclin A2. Furthermore, luteoloside induced apoptosis and promoted differentiation of AML cells. Activation of Wnt/ß-catenin signaling by GSK3ß inhibitor LiCl reversed the inhibitory effect of luteoloside on AML cell proliferation, apoptosis, and differentiation, due to ß-catenin entering into nucleus and reducing the expression of c-Myc. Luteoloside significantly reduced the transplantation rate of primary AML cells in PDX model, and the combination of luteoloside and cytarabine showed a synergistic anti-AML effect in orthotopic AML model. Conclusion: Our findings demonstrate that luteoloside inhibits proliferation, induces apoptosis and differentiation of AML cells via suppression of ß-catenin/c-Myc axis, suggesting that luteoloside can be developed as a potential anti-AML drug. Overall design: U937 cells were treated with luteoloside or DMSO for 72h and harvested for RNA-seq to investigate the mechanism of luteoloside on AML.