Title : Repurposing of atovaqoune for treatment of FLT3-ITD quizartinib sensitive and resistant acute myeloid leukemia
Abstract:
FLT3-ITD is the most common mutation in acute myeloid leukemia (AML). Despite the clinical availability of some targeted agents against AML, including a recently approved FLT3 inhibitor, quizartinib, the poor survival rate and drug resistance remain a problem. Here, we explore the effect of atovaquone an FDA-approved, anti-malarial drug on MOLM-13 quizartinib sensitive and resistant cell lines as a cellular model for FLT3-ITD AML. 30 µM atovaquone treatment significantly induced apoptosis by >80% in both cell lines after 96 h. The Seahorse XF96 Cell Mito Stress Test indicated that after 24 h of treatment with 30 µM atovaquone, the oxygen consumption rate parameters including basal respiration, maximal mitochondrial respiration and ATP production were reduced by >85% in both cell lines, compared to untreated cells. Indeed, 10 µM treatment reduced all the parameters by >50% in quizartinib sensitive cells. ROS elevated by 50-fold on FLT3-ITD sensitive (p<0.0001) and 29- fold in FLT3-ITD resistant (p<0.001). Finally, RNA seq analysis shows significant downregulation of cell cycle and oxidative phosphorylation in both cell lines. In conclusion, at a clinically relevant concentration, atovaquone exerts its antileukemic effect in FLT3-ITD quizartinib sensitive and resistant cells by increasing oxidative stress leading to cell death.
