Jakobsson Amanda Westergren, Kundu Snehangshu, Guo Jing, Chowdhury Azazul, Zhao Miao, Lindell Emma, Bergsten Peter, Swartling Fredrik J, Sjöblom Tobias, Zhang Xiaonan
Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden.
Centre for Computational Biology, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
Cancers (Basel). 2022 Jun 30;14(13):3225. doi: 10.3390/cancers14133225.
Neuroblastoma, the most common solid tumor in children, is characterized by amplification of the 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.
神经母细胞瘤是儿童最常见的实体瘤，其特征是原癌基因扩增，这是一种与治疗失败相关的高风险侵袭性临床标志物。MYCN在细胞生长、增殖、代谢和化疗耐药性中起重要作用。在此，我们首次表明，在神经母细胞瘤中，铁螯合剂VLX600抑制线粒体呼吸，降低MYCN/LMO1的表达水平，并在二维和三维培养条件下，无论MYCN状态如何，均能诱导有效的细胞死亡。此外，在用VLX600处理的细胞中观察到自噬诱导不足，而自噬在ATP合成中断时作为一种保护性反应至关重要。使用泛葡萄糖转运蛋白（GLUT）抑制剂DRB18进一步抑制葡萄糖摄取，可增强VLX600的作用，并且在这种联合治疗下，永生化上皮细胞中未发现明显的细胞死亡。我们的结果表明，铁螯合剂VLX600抑制线粒体呼吸并伴有自噬缺陷，可在营养受限的微环境中提高神经母细胞瘤细胞的敏感性，而与MYCN状态无关，这表明MYCN表达水平是一个重要的临床标志物，但可能不是神经母细胞瘤治疗的必要靶点，这值得进一步研究。VLX600已在I期临床试验中进行了研究；将VLX600与传统化疗联合使用可能是治疗神经母细胞瘤的一种创新治疗策略。
