Neuroblastoma Differentiation: The Untapped Potential of Mitochondrial Uncouplers

Abstract

While the goal of most anticancer treatments is to kill cancer cells, some therapies halt cancer progression by inducing cancer cell differentiation. For example, retinoic acid induces neuroblastoma cell differentiation in vitro and is used as maintenance therapy for children with high-risk neuroblastoma. A new study by Jiang and colleagues has revealed the mitochondrial uncoupler niclosamide ethanolamine (NEN) induces neuroblastoma cell differentiation in vitro and slows neuroblastoma tumor growth in vivo. Mitochondrial uncoupler molecules alter cell metabolism by forcing cells to "burn" more nutrients, resulting in a switch from anabolic to catabolic metabolism. NEN-induced neuroblastoma cell differentiation was associated with disruption of Warburg metabolism, epigenetic remodeling, and downregulation of key oncogenic drivers of neuroblastoma development, including MYCN. NEN is currently used as an antiparasitic worm treatment and is safe to use in children but has poor pharmacokinetic properties. However, derivatives of NEN and structurally distinct uncouplers that have improved pharmacokinetic properties are in development. Results of this study ignite the idea that mitochondrial uncouplers could be used as differentiating agents and expand the pharmacotherapy toolkit to treat cancer, including neuroblastoma. See related article by Jiang et al., p. 181.