Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, 601 77 Brno, Czech Republic.
International Clinical Research Center, St. Anne's University Hospital, 656 91 Brno, Czech Republic.
Int J Mol Sci. 2021 Dec 29;23(1):376. doi: 10.3390/ijms23010376.
Despite constant advances in the field of pediatric oncology, the survival rate of high-risk neuroblastoma patients remains poor. The molecular and genetic features of neuroblastoma, such as amplification and stemness status, have established themselves not only as potent prognostic and predictive factors but also as intriguing targets for personalized therapy. Novel thiosemicarbazones target both total level and activity of a number of proteins involved in some of the most important signaling pathways in neuroblastoma. In this study, we found that di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) potently decreases N-MYC in -amplified and c-MYC in -nonamplified neuroblastoma cell lines. Furthermore, DpC succeeded in downregulating total EGFR and phosphorylation of its most prominent tyrosine residues through the involvement of NDRG1, a positive prognostic marker in neuroblastoma, which was markedly upregulated after thiosemicarbazone treatment. These findings could provide useful knowledge for the treatment of MYC-driven neuroblastomas that are unresponsive to conventional therapies.
尽管儿科肿瘤学领域不断取得进展，但高危神经母细胞瘤患者的生存率仍然较低。神经母细胞瘤的分子和遗传特征，如扩增和干性状态，不仅确立了自身作为强大的预后和预测因素，而且作为个性化治疗的有趣靶点。新型硫代乙内酰脲靶向参与神经母细胞瘤中一些最重要信号通路的许多蛋白质的总水平和活性。在这项研究中，我们发现二吡啶酮 4-环己基-4-甲基-3-硫代乙内酰脒（DpC）可有效降低扩增型 N-MYC 和非扩增型 c-MYC 在神经母细胞瘤细胞系中的表达。此外，DpC 通过 NDRG1（神经母细胞瘤的一个阳性预后标志物）成功下调了总 EGFR 和其最显著的酪氨酸残基的磷酸化，NDRG1 在硫代乙内酰脲处理后明显上调。这些发现可为治疗对常规治疗无反应的 MYC 驱动型神经母细胞瘤提供有用的知识。
