Luteoloside Inhibits the Progression and Enhances Chemosensitivity to Cytarabine in Acute Myeloid Leukemia via β‐Catenin/c‐Myc Axis

Acute myeloid leukemia (AML) is one of the most common and lethal hematologic malignancies with limited possibilities for treatment. Thus, more effective therapeutic drugs are imperatively needed to fulfill current unmet medical requirements. Luteoloside, derived from the traditional Chinese medicine Lonicera japonica, demonstrates potent anti-tumor activity against solid tumors, but its effects and mechanisms in hematologic malignancies like AML remain unclear. Herein, we found that luteoloside dramatically impaired the proliferation and clonogenic capacity of AML cells and induced cell cycle arrest and reduced the cells at S phase. Furthermore, luteoloside induced apoptosis and promoted differentiation of these cells. Mechanism analysis revealed that luteoloside attenuated β-catenin in the nucleus, thereby reducing the expression of its downstream effector c-Myc. Activation of Wnt/β-catenin signaling by a GSK-3β inhibitor LiCl reversed the inhibitory effect of luteoloside on AML cell proliferation, apoptosis, and differentiation. Luteoloside significantly reduced the transplantation rate of primary AML cells in a patient-derived xenografts (PDX) model. Combined treatment with luteoloside and cytarabine (Ara-C) showed a synergistic anti-AML effect in vitro, and markedly reduced leukemia burden and prolonged the survival in the orthotopic C1498 murine AML model. Collectively, our findings demonstrate that luteoloside suppresses AML cell proliferation, induces apoptosis and differentiation by targeting the β-catenin/c-Myc axis, and exhibits synergistic effects with Ara-C. These results underscore its potential as a promising adjunctive therapy for AML.