Pharmacologically Targeting Ferroptosis and Cuproptosis in Neuroblastoma

Abstract

Neuroblastoma is a deadly pediatric cancer that originates from the neural crest and frequently develops in the abdomen or adrenal gland. Although multiple approaches, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy, are recommended for treating neuroblastoma, the tumor will eventually develop resistance, leading to treatment failure and cancer relapse. Therefore, a firm understanding of the molecular mechanisms underlying therapeutic resistance is vital for the development of new effective therapies. Recent research suggests that cancer-specific modifications to multiple subtypes of nonapoptotic regulated cell death (RCD), such as ferroptosis and cuproptosis, contribute to therapeutic resistance in neuroblastoma. Targeting these specific types of RCD may be viable novel targets for future drug discovery in the treatment of neuroblastoma. In this review, we summarize the core mechanisms by which the inability to properly execute ferroptosis and cuproptosis can enhance the pathogenesis of neuroblastoma. Therefore, we focus on emerging therapeutic compounds that can induce ferroptosis or cuproptosis, delineating their beneficial pharmacodynamic effects in neuroblastoma treatment. Cumulatively, we suggest that the pharmacological stimulation of ferroptosis and ferroptosis may be a novel and therapeutically viable strategy to target neuroblastoma.

Keywords: Ferroptosis; Compounds; Cuproptosis; Neuroblastoma.

Fig. 1

Core mechanisms of ferroptosis

Fig. 2

Basic core mechanisms of cuproptosis. The uptake of Cu²⁺ into cells occurs via solute carrier family 31 member 1 (SLC31A1) or copper ionophores. Cu²⁺ then binds selectively to lipoylated tricarboxylic acid cycle proteins and mediates Fe-S cluster protein instability to induce a toxic gain of function through mitochondrial proteotoxic stress, namely, copper-dependent oligomerization of lipoylated proteins, eventually leading to cell death. Elesclomol functions as a copper ionophore to transport copper into cells. The copper importers SLC31A1 and the copper exporter ATPase copper-transporting beta (ATP7B) can also regulate intracellular copper levels. Ferredoxin 1 (FDX1) can reduce Cu²⁺ to Cu⁺ and subsequently lipoylates mitochondrial tricarboxylic acid (TCA) cycle enzymes, especially dihydrolipoamide S-acetyltransferase (DLAT), to promote Fe-S cluster protein loss. Copper-mediated damage to the mitochondrial respiratory chain causes hyperactivation of the energy sensor AMPK, which accelerates cuproptosis and the release of the proinflammatory mediator HMGB1. LA-DLAT, lipoylated DLAT; LIAS, lipoyl synthase

Fig. 3

Chemical structures of small molecules that target ferroptosis to treat neuroblastoma