Iron Chelator VLX600 Inhibits Mitochondrial Respiration and Promotes Sensitization of Neuroblastoma Cells in Nutrition-Restricted Conditions

by Selleckchem | Sep 17 2023

Neuroblastoma, the most common solid tumor in children, is characterized by amplification of the MYCN proto-oncogene, a high-risk aggressive clinical marker associated with treatment failure. MYCN plays an important role in cell growth, proliferation, metabolism, and chemoresistance. Here, we show for the first time that in neuroblastoma, iron chelator VLX600 inhibits mitochondrial respiration, decreases expression levels of MYCN/LMO1, and induces an efficient cell death regardless of MYCN status in both 2D and 3D culture conditions. Moreover, insufficient induction of autophagy was observed in cells treated with VLX600, which is essential as a protective response in the event of ATP synthesis disruption. Further inhibition of glucose uptake using DRB18, a pan-GLUT (glucose transporter) inhibitor, synergized the effect of VLX600 and no significant cell death was found in immortalized epithelial cells under this combination treatment. Our results demonstrate that inhibition of mitochondrial respiration by iron chelator VLX600 accompanied by autophagy deficiency promotes sensitivity of neuroblastoma cells in a nutrition-restricted microenvironment regardless of MYCN status, indicating that MYCN expression level is an essential clinical marker but might not be a necessary target for the treatment of neuroblastoma which warrants further investigation. VLX600 has been studied in Phase I clinical trials; combining VLX600 with conventional chemotherapy could be an innovative therapeutic strategy for neuroblastoma.

Comments:

Neuroblastoma is a common solid tumor found in children and is associated with amplification of the MYCN proto-oncogene, which is a marker of aggressive disease and poor treatment outcomes. MYCN plays a crucial role in various cellular processes such as cell growth, proliferation, metabolism, and chemoresistance. In a recent study, it has been shown that the iron chelator VLX600 can effectively inhibit mitochondrial respiration, decrease the expression levels of MYCN/LMO1, and induce cell death in both 2D and 3D culture conditions in neuroblastoma cells. Importantly, this effect was observed regardless of the MYCN status of the cells.

Furthermore, the study revealed that treatment with VLX600 resulted in insufficient induction of autophagy, which is a protective cellular response that helps maintain ATP synthesis in case of disruptions. This deficiency in autophagy contributed to the increased sensitivity of neuroblastoma cells to VLX600, particularly in a nutrition-restricted microenvironment. Additionally, the researchers investigated the combination of VLX600 with DRB18, a pan-GLUT (glucose transporter) inhibitor that further inhibits glucose uptake. This combination treatment synergized the effect of VLX600, leading to significant cell death in neuroblastoma cells, while not causing significant cell death in immortalized epithelial cells.

These findings suggest that inhibiting mitochondrial respiration with the iron chelator VLX600, along with autophagy deficiency, can enhance the sensitivity of neuroblastoma cells to treatment, irrespective of MYCN status. While MYCN expression remains an essential clinical marker, this study implies that targeting MYCN directly may not be necessary for the treatment of neuroblastoma. Further investigation is warranted to explore the potential of combining VLX600 with conventional chemotherapy, as VLX600 has already been studied in Phase I clinical trials. This combination could represent an innovative therapeutic strategy for neuroblastoma.