The Protozoan Inhibitor Atovaquone Affects Mitochondrial Respiration and Shows In Vitro Efficacy Against Glucocorticoid-Resistant Cells in Childhood B-Cell Acute Lymphoblastic Leukaemia

Childhood acute lymphoblastic leukaemia (cALL) accounts for about one third of all paediatric malignancies making it the most common cancer in children. Alterations tumour cell metabolism were first described nearly a century ago and have been acknowledged as key characteristics cancers including cALL. Two backbone chemotherapeutic agents treatment this disease, Glucocorticoids L-asparaginase, are exerting their anti-leukaemic effects through targeting metabolism. Even though risk stratification regimens improved cure rates to 90%, prognosis relapsed children remains poor. Therefore, new therapeutic approaches urgently required. Atovaquone is well-tolerated drug used clinic mainly against malaria. Being ubiquinone analogue, inhibits co-enzyme Q10 electron transport chain (ETC) affecting oxidative phosphorylation In study we tested effect on cALL cells vitro . Pharmacologically relevant concentrations inhibitor could effectively target mitochondrial respiration both lines (REH Sup-B15) primary patient samples. We found that leads marked decrease basal ATP levels, well reduced proliferation, cycle arrest, induction apoptosis. Importantly, observed an enhanced when was combined with standard Idarubicin, or Prednisolone model Glucocorticoid resistance. Repurposing clinically approved renders further investigations, but also presents opportunities fast-track trials single agent combination chemotherapeutics.