Ferric citrate and Arsenic Trioxide: A Potent Duo Against Neuroblastoma Through Ferroptosis Activation

Abstract Background Iron exhibits a close association with neuroblastoma (NB), as elevated serum ferritin is frequently observed in high-risk NB and correlates with an unfavorable prognosis. Ferroptosis, a recently identified cell death modality characterized by iron-dependent lipid peroxidation, involves the crucial triggering role of intracellular free iron overload. Methods In this study, we assessed the cellular activity, cellular morphology and reactive oxygen species (ROS) levels in response to ferric citrate (FAC), ATO, and their combination in NB cell lines SK-N-AS and SH-SY5Y. Subsequently, a rescue assay was employed to confirm that the primary mode of NB cell death induced by ATO in conjunction with FAC was ferroptosis. Results FAC augmented the inhibitory effects of ATO on NB cells. Increasing FAC concentrations did not significantly promote the proliferation of SK-N-AS and SH-SY5Y NB cell lines. The inhibitory impact of ATO on the proliferation of these NB cell lines was more pronounced with elevated ferroptosis indicators, ROS, in combination with FAC. Moreover, treatment with the ferroptosis inhibitor Fer-1 alleviated the inhibitory effects of ATO in combination with FAC on the two NB cell lines. Conclusion Our findings suggest that FAC does not notably contribute to tumor growth but enhances the inhibitory effects of ATO on NB cells. This indicates the potential of FAC combined with ATO as a treatment strategy for NB.