The FTO inhibitor Rhein is a promising option for the treatment of multidrug resistance AML

Abstract

Abstract Purpose Chemotherapy failure and resistance contribute to poor prognosis in Acute Myeloid Leukemia (AML)patients. The fat mass and obesity-associated protein (FTO) is dysregulated and plays crucial roles in AML. we aim in exploring what role the FTO inhibitor Rhein played in multidrug resistance AML. Methods Bone marrow fluid was collected to clarify FTO expression in AML. Cell Counting Kit 8 reagent(CCK8) was used to detect the inhibition of proliferation. Migration assays were conducted using 24-well transwell chambers with 8-µm apertures. And flow cytometry and WB assays were used to clarify apoptotic effects of rhein and proteins changes. The online SynergyFinder software was utilized to calculate drug synergy scores. Results We observed that FTO is overexpressed in AML, particularly in AML occurred multidrug resistance. Rhein significantly suppresses proliferation and migration in parent and multidrug-resistant AML cells in a dose- and time-dependent manner. In particular, multidrug-resistant AML cells did not show resistance to Rhein. Furthermore, Rhein promotes apoptosis and decreased the expression of Bcl-2 while increasing the expression of Bax. Additionally, Rhein suppressed FTO expression and inhibited the AKT/mTOR signaling pathways. We also identified that low-dose Rhein in combination with AZA could sensitize HL60 and HL60-ADR cells to AZA. Conclusion Rhein significantly suppresses proliferation and migration, promotes apoptosis, sensitive to multidrug-resistant AML cells, is a promising candidate for treating multidrug-resistant AML.