Iron-Chelation Treatment by Novel Thiosemicarbazone Targets Major Signaling Pathways in Neuroblastoma

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Authors

MACSEK Peter ŠKODA Jan KRCHNIAKOVÁ Mária NERADIL Jakub VESELSKÁ Renata

Year of publication 2022
Type Article in Periodical
Magazine / Source International Journal of Molecular Sciences
MU Faculty or unit

Faculty of Science

Citation
Web https://www.mdpi.com/1422-0067/23/1/376
Doi http://dx.doi.org/10.3390/ijms23010376
Keywords thiosemicarbazone; DpC; neuroblastoma; MYC; EGFR; NDRG1; lipid droplet
Description 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 MYCN 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 MYCN-amplified and c-MYC in MYCN-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.
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