Rhein exerts anti-multidrug resistance in acute myeloid leukemia via targeting FTO to inhibit AKT/mTOR

Chemotherapy failure and resistance are the leading causes of mortality in patients with acute myeloid leukemia (AML). However, the role of m6A demethylase FTO and its inhibitor rhein in AML and AML drug resistance is unclear. Therefore, this study aimed to investigate the antileukemic effect of rhein on AML and explore its potential mechanisms underlying drug resistance. Bone marrow fluid was collected to assess FTO expression in AML. The Cell Counting Kit 8 reagent was used to assess cell viability. Migration assays were conducted to assess the cell migration capacity. Flow cytometry was used to determine the apoptotic effects of rhein and western blot analysis was used to detect protein expression. Online SynergyFinder software was used to calculate the drug synergy scores. The in-vivo antileukemic effect of rhein was assessed in an AML xenograft mouse model. We analyzed different types of AML bone marrow specimens to confirm that FTO is overexpressed in AML, particularly in cases of multidrug resistance. Subsequently, we conducted in-vivo and in-vitro investigations to explore the pharmacological activity and mechanism of rhein in AML and AML with multidrug resistance. The findings demonstrated that rhein effectively suppressed the proliferation and migration of AML cells in a time- and dose-dependent manner and induced apoptosis. Rhein targets FTO, inhibits the AKT/mTOR pathway, and exhibits synergistic antitumor effects when combined with azacitidine. This study elucidates the significant role of FTO and its inhibitor rhein in AML and AML with multidrug resistance, providing new insights for overcoming multidrug resistance in AML.